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Likely inborn error of metabolism - targeted testing not possible v4.117 VPS33A Sarah Leigh gene: VPS33A was added
gene: VPS33A was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: VPS33A.
Mode of inheritance for gene: VPS33A was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS33A were set to 28013294; 27547915; 31070736
Phenotypes for gene: VPS33A were set to Mucopolysaccharidosis-plus syndrome OMIM:617303; mucopolysaccharidosis-like syndrome with congenital heart defects and hematopoietic disorders MONDO:0015012
Review for gene: VPS33A was set to GREEN
Added comment: This gene has been copied from Lysosomal storage disorder panel:
Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least one variant was reported in two Turkish sisters (PMID 27547915) and in the Yakut population in the Russian Federation (PMID 28013294), where haplotype evidence suggested a founder effect in the Russian population. Supportive functional studies were also presented (PMID 31070736).
Sarah Leigh (Genomics England Curator), 17 Mar 2021
Single variant (R498W) reported in the Turkish and Yakut population. Functional studies support association of this gene to lysosomal dysfunction. Sources: Expert list
Zornitza Stark (Australian Genomics), 22 Jul 2020
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.115 VPS16 Sarah Leigh Added comment: Comment on mode of inheritance: Biallelic variants are associated with a phenotype resembling a lysosomal storage disease. There are sufficient families (3) and functional data showing defects in the endolysosomal trafficking system to support inclusion for this allelic requirement. Monoallelic variants are linked to dystonia but only one study performed further analyses that suggested lysosomal dysfunction. Therefore while possible, it is unclear whether the 'Lysosomal storage disorder' panel would be applied in these cases. VPS16 will be flagged for GMS review with regards to the most appropriate MOI on this panel (biallelic or both bilalleic/monoallelic)
Arina Puzriakova (Genomics England Curator), 14 Jun 2021
Likely inborn error of metabolism - targeted testing not possible v4.114 VPS16 Sarah Leigh gene: VPS16 was added
gene: VPS16 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: VPS16.
Mode of inheritance for gene: VPS16 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: VPS16 were set to 33938619; 34013567
Phenotypes for gene: VPS16 were set to Mucopolysaccharidosis-like syndrome (biallelic); Dystonia Associated with Lysosomal Abnormalities (monoallelic); Dystonia 30, OMIM:619291
Review for gene: VPS16 was set to GREEN
Added comment: Copied from Lysosomal storage disorder panel: Four individuals from three families were identified (PMIDs: 33938619; 34013567) exhibiting a mucopolysaccharidosis (MPS)-like lysosomal storage phenotype with short stature, coarse facies, DD or regression, peripheral neuropathy, skeletal dysplasia, neutropenia, and high-normal glycosaminoglycan excretion. All harboured homozygous variants in VPS16 which segregated with disease, including a missense variant in a sib pair (c.540G>T; p.Trp180Cys) and a recurrent intronic variant (c.2272‐18C>A) in two supposedly unrelated patients (although both of Middle Eastern descent). Fibroblasts of the two patients with the intronic variant showed accumulation of lysosomal compartments and autophagosomes with significantly decreased VPS16 mRNA and protein levels, as well as HOPS/CORVET complexes. Cellular phenotypes were rescued upon re-expression of wild-type VPS16. ----- Heterozygous variants, as well as a homozygous missense variant (c.156C>A) found in a consanguineous Chinese family (PMID:27174565), have been found to cause dystonia with variable onset (OMIM:619291). It has been suggested that the discrepancies in patient phenotypes are due to different mechanisms of pathogenicity, where variants causing dystonia do not affect the levels of endolysosomal tethering (HOPS/CORVET) complexes. More research is needed to clarify the mechanisms underlying VPS16-related dystonia as only limited functional data is currently available - Steel et al. 2020 (PMID:32808683) did perform electron microscopic studies of lymphocytes and fibroblasts derived from 2 unrelated patients, which showed vacuolar abnormalities suggestive of impaired lysosomal function. Sources: Literature
Arina Puzriakova (Genomics England Curator), 14 Jun 2021
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.101 EDEM3 Sarah Leigh gene: EDEM3 was added
gene: EDEM3 was added to Likely inborn error of metabolism - targeted testing not possible. Sources: Other
Q4_23_promote_green tags were added to gene: EDEM3.
Mode of inheritance for gene: EDEM3 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: EDEM3 were set to 34143952
Phenotypes for gene: EDEM3 were set to Congenital disorder of glycosylation, type 2V, OMIM:619493
Review for gene: EDEM3 was set to GREEN
Added comment: Reviews copied from entry on Congenital disorders of glycosylation panel.
There is sufficient evidence to promote this gene to Green at the next GMS panel update. EDEM3 is associated with a relevant phenotype in OMIM (MIM# 619493) and G2P with a 'strong' confidence level assertion. 12 individuals from 7 unrelated families identified by Polla et al. 2021 (PMID: 34143952) with various biallelic variants in the EDEM3 gene. Clinical characteristics were predominant for DD (12/12), ID (6/7), hypotonia (6/12) and facial dysmorphisms. (Arina Puzriakova (Genomics England Curator), 18 Jul 2022).
PMID: 34143952: 7 families (11 individuals) with 6x PTV and 2x missense variants with neurodevelopmental delay and variable facial dysmorphisms. The unaffected parents were all heterozygous carriers. Functional studies show loss of EDEM3 enzymatic activity. Sources: Literature (Zornitza Stark (Australian Genomics), 7 Aug 2021).
Sources: Other
Likely inborn error of metabolism - targeted testing not possible v4.77 ATP5B Sarah Leigh commented on gene: ATP5B: In the opinion of Helen Brittain (Clinical Fellow, Genomics England) is "There is a lack of clarity over the penetrance, plus also the phenotypes are somewhat disparate (the twins had DD with episodic hyperthermia, whereas the other cases presented with dystonia). A gene:disease association cannot be made at this time".
Likely inborn error of metabolism - targeted testing not possible v2.263 EXT1 Arina Puzriakova commented on gene: EXT1: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Likely inborn error of metabolism - targeted testing not possible v2.263 DHTKD1 Arina Puzriakova commented on gene: DHTKD1: The recent MOI update on this panel was done following an audit of genes with different MOIs on component panels of the same superpanel. These were reviewed by the curation team accounting for respective panel scope and final MOIs were validated by the Genomics England clinical team.
Likely inborn error of metabolism - targeted testing not possible v2.144 FAR1 Arina Puzriakova Added comment: Comment on list classification: In view of the normal metabolic screening (excluding very specific functional work, which will not be in routine NHS practice) there is no clear alignment with the metabolic panels and therefore FAR1 should be demoted from Green to Red at the next GMS panel update (discussed with Helen Brittain, Genomic England Clinical Team)
Likely inborn error of metabolism - targeted testing not possible v2.127 OPA1 Sarah Leigh Added comment: Comment on phenotypes: Optic atrophy plus syndrome, 125250;{Glaucoma, normal tension, susceptibility to}, 606657;Disorders of mitochondrial DNA maintenance and integrity;Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions;Optic atrophy 1, 165500;Mitochondrial DNA Depletion Syndrome;Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only))
Likely inborn error of metabolism - targeted testing not possible v2.127 OPA1 Sarah Leigh Phenotypes for gene: OPA1 were changed from Optic atrophy plus syndrome, 125250; {Glaucoma, normal tension, susceptibility to}, 606657; Disorders of mitochondrial DNA maintenance and integrity; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions; Optic atrophy 1, 165500; Mitochondrial DNA Depletion Syndrome; Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) to ?Mitochondrial DNA depletion syndrome 14 (encephalocardiomyopathic type) OMIM:616896; mitochondrial DNA depletion syndrome 14 (cardioencephalomyopathic type) MONDO:0014820; Optic atrophy 1 OMIM:165500; autosomal dominant optic atrophy, classic form MONDO:0008134; Optic atrophy plus syndrome OMIM:125250; optic atrophy with or without deafness, ophthalmoplegia, myopathy, ataxia, and neuropathy MONDO:0007429; Behr syndrome OMIM:210000; Behr syndrome MONDO:0008858
Likely inborn error of metabolism - targeted testing not possible v2.50 GLS_GCA Arina Puzriakova Added comment: Comment on list classification: There are sufficient unrelated cases and supportive functional data for inclusion as diagnostic-grade.

However, detection of this 5' UTR triplet expansion must first be validated within the Genomics England pipeline. In the meantime, rating Red but will raise the STR for validation with the Rare Disease team.
Likely inborn error of metabolism - targeted testing not possible v2.48 GLS Arina Puzriakova Added comment: Comment on list classification: There are sufficient cases, supported by functional data, to rate this gene Green - however, detection of the 5' UTR triplet expansion (PMID:30970188) has not yet been validated within the Genomics England pipeline.

When excluding cases with the STR, the remaining evidence is not sufficient for inclusion as diagnostic-grade and therefore this gene is tagged 'for-review' to assess whether it should be downgraded to Amber until the STR is validated or additional cases arise.
Likely inborn error of metabolism - targeted testing not possible v2.44 NUS1 Eleanor Williams Added comment: Comment on list classification: Promoting from red to amber on advice from Genomics England clinical team. 1 case plus some functional data.
Likely inborn error of metabolism - targeted testing not possible v2.1 PCYT2 Sarah Leigh gene: PCYT2 was added
gene: PCYT2 was added to Inborn errors of metabolism. Sources: Literature
Mode of inheritance for gene: PCYT2 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: PCYT2 were set to 31637422; 17325045; 22764088
Phenotypes for gene: PCYT2 were set to Global developmental delay; Developmental regression; Intellectual disability; Spastic paraparesis; Seizures; Spastic tetraparesis; Cerebral atrophy; Cerebellar atrophy
Review for gene: PCYT2 was set to RED
Added comment: This gene was added by an external reviewer and rated Green on Hereditary spastic paraplegia gene panel (Version 1.210), and confirmed with Zerin Hyder (Genomics England Clinical Team) that this is appropriate to be Green on the Inborn errors of metabolism panel. The rating of this gene will be changed when the next reiteration of this panel is made.
Sources: Literature
Likely inborn error of metabolism - targeted testing not possible v1.336 ISCA2 Sarah Leigh Added comment: Comment on list classification: Associated with relevant phenotype in OMIM, but not associated with phenotype in Gen2Phen. At least 3 variants reported in two different ethinicities.
Rated green based on review of Anna de Burca (Clinical Fellow, Genomic England).
Likely inborn error of metabolism - targeted testing not possible v1.311 ATP5A1 Sarah Leigh changed review comment from: Comment on list classification: The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.; to: Comment on list classification: This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys mentioned in this article have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Likely inborn error of metabolism - targeted testing not possible v1.287 STAT2 Sarah Leigh Added comment: Comment on list classification: Based on recommendation of Helen Britain (Clinical Fellow, Genomics England), that the majority of cases will be presenting in the context of overwhelming infection. The raised lactate and encephalomyopathy are potentially relevant phenotypes for this panel, however more evidence is needed on how common this presentation is, and whether it is always clearly associated with a proven infection.
Likely inborn error of metabolism - targeted testing not possible v1.286 SPTLC1 Catherine Snow changed review comment from: Promoted from Amber to Green. This gene is associated with a relevant disease in OMIM and there is enough evidence to support a gene-disease association.

SPTLC1, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID 20097765 reports that mutations in SPTLC1 cause a gain of function mechanism, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.

Confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/) and in sufficient publications.; to: Promoted from Amber to Green. This gene is associated with a relevant disease in OMIM and there is enough evidence to support a gene-disease association.

SPTLC1, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID 20097765 reports that mutations in SPTLC1 cause a gain of function mechanism, which results in the formation of two atypical and neurotoxic sphingolipid metabolites.

Confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/) and in sufficient publications.

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Likely inborn error of metabolism - targeted testing not possible v1.281 SPTLC2 Catherine Snow changed review comment from: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.
SPTLC2, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID: 20920666 reports on three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families and also confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/).
This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.; to: Promoted from Amber to Green. This gene is associated with a relevant disease on OMIM and Gene2Phenotype and there is enough evidence to support a gene-disease association.

SPTLC2, encodes one of the two subunits of serine palmitoyltransferase (SPT), the enzyme catalyzing the first and rate-limiting step in the de novo synthesis of sphingolipids. PMID: 20920666 reports on three heterozygous missense mutations in the SPTLC2 subunit of SPT in four families and also confirmed cases in Bristol (see review on Hereditary Neuropathy panel https://panelapp.genomicsengland.co.uk/panels/85/).

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype.
Likely inborn error of metabolism - targeted testing not possible v1.278 IER3IP1 Sarah Leigh changed review comment from: Comment on list classification: IER3IP1 has been demoted to Red on the Mitochondrial disorders panel on the recommendation of the GMS mitochondrial specialist test group, including by Carl Fratter (Oxford University Hospitals NHS Trust). It is associated with Microcephaly, epilepsy, and diabetes syndrome 614231, which is not technically a mitochondrial disorder, as the phenotype is quite different to other mitochondrial conditions, thus in the opinion of Helen Britain the phenotypes reported, the condition could initially present as a mimic of a mitochondrial presentation e.g. abnormal liver enzymes, diabetes, neurological dysfunction and therefore a green rating on metabolic panels would seem appropriate.; to: Comment on list classification: IER3IP1 has been demoted to Red on the Mitochondrial disorders panel on the recommendation of the GMS mitochondrial specialist test group, including by Carl Fratter (Oxford University Hospitals NHS Trust). It is associated with Microcephaly, epilepsy, and diabetes syndrome 614231, which is not technically a mitochondrial disorder, as the phenotype is quite different to other mitochondrial conditions. Thus in the opinion of Helen Britain (Genomics England Clinical Fellow) the phenotypes reported could initially present as a mimic of a mitochondrial presentation e.g. abnormal liver enzymes, diabetes, neurological dysfunction and therefore a green rating on metabolic panels would seem appropriate.
Likely inborn error of metabolism - targeted testing not possible v1.243 ATP5A1 Sarah Leigh Added comment: Comment on list classification: The Amber rating is based on the views of Anna de Burca (Genomics England Clinical Fellow) that the interpretation of PMID 23599390 that the boys have inherited a heterozygous variant from their father while not expressing the maternal allele due to unknown variant affecting expression.
Likely inborn error of metabolism - targeted testing not possible v1.71 RANBP2 Sarah Leigh Added comment: Comment on list classification: Demoted RANBP2 from Green to Amber following review by Zornitza Stark and agreement from Helen Brittain (Genomics England clinical team). Recent papers report patients with symptoms (including seizures) after a viral illness (PMID:30796099, PMID:28336122, PMID:25128471). However, listed as a susceptibility locus in OMIM, and papers report incomplete penetrance: variant present in asymptomatic maternal grandmother in PMID:30796099 and in the father in PMID:28336122. Therefore further information (e.g. on penetrance) is required for a clear gene:disease association.
Likely inborn error of metabolism - targeted testing not possible v1.47 GLA Ivone Leong Source NHS GMS was added to GLA.
Source London North GLH was added to GLA.
Likely inborn error of metabolism - targeted testing not possible v0.4 GLA Ellen McDonagh gene: GLA was added
gene: GLA was added to Inborn errors of metabolism. Sources: Expert Review Green
Mode of inheritance for gene: GLA was set to X-LINKED: hemizygous mutation in males, monoallelic mutations in females may cause disease (may be less severe, later onset than males)
Publications for gene: GLA were set to 27604308
Phenotypes for gene: GLA were set to Fabry disease, cardiac variant, 301500; Fabry Disease; Fabry disease (Sphingolipidoses); Fabry disease, 301500
Likely inborn error of metabolism - targeted testing not possible v0.4 OPA1 Ellen McDonagh Added phenotypes Optic atrophy plus syndrome, 125250; {Glaucoma, normal tension, susceptibility to}, 606657; Disorders of mitochondrial DNA maintenance and integrity; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions; Optic atrophy 1, 165500; Mitochondrial DNA Depletion Syndrome; Disorders of mitochondrial dynamics, fusion and fission (Mitochondrial respiratory chain disorders (caused by nuclear variants only)) for gene: OPA1
Publications for gene OPA1 were changed from to 27604308
Likely inborn error of metabolism - targeted testing not possible v0.4 OPA1 Ellen McDonagh gene: OPA1 was added
gene: OPA1 was added to Inborn errors of metabolism. Sources: Expert Review Green
Mode of inheritance for gene: OPA1 was set to BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal
Phenotypes for gene: OPA1 were set to Optic atrophy plus syndrome, 125250; {Glaucoma, normal tension, susceptibility to}, 606657; Disorders of mitochondrial DNA maintenance and integrity; Progressive External Ophthalmoplegia with Mitochondrial DNA Deletions; Optic atrophy 1, 165500; Mitochondrial DNA Depletion Syndrome