Intellectual disability - microarray and sequencing
Gene: HNMT Green List (high evidence)The rating of this gene has been updated following NHS Genomic Medicine Service approval.Created: 14 Mar 2022, 2:22 p.m. | Last Modified: 14 Mar 2022, 2:22 p.m.
Panel Version: 3.1519
Green List (high evidence)
This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype. Based on the expert reviews and available information, there is enough evidence to support a gene-disease association. This gene should be rated Green at the next review.Created: 17 Aug 2021, 10:12 a.m. | Last Modified: 17 Aug 2021, 10:12 a.m.
Panel Version: 3.1227
Green List (high evidence)
In addition to the two unrelated families reported by Heidari et al. 2015 (PMID: 26206890), two further simplex cases with homozygous HNMT variants have been reported, providing sufficient evidence for a 'green' classification. Verhoeven et al. 2020 (PMID: 33310825) report an adult male patient with severe intellectual disability and autism, born to second cousins, with a homozygous nonsense variant (c.88C>T; p.Gln30*). Treatment with antihistaminergic medication and a histamine-restricted diet resulted in significant general improvement, supporting an etiological role for HNMT deficiency. Taskiran et al. 2021 (PMID: 33739554) report an adult male patient with severe intellectual disability, pervasive developmental disorder and ADHD, born to consanguineous parents, with a homozygous nonsense variant (c.100G>T; p.Glu34*).Created: 13 Aug 2021, 9:10 a.m. | Last Modified: 13 Aug 2021, 9:10 a.m.
Panel Version: 3.1220
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability; 616739
Publications
I don't know
Comment on list classification: Amber rating as additional unrelated pedigrees are required before inclusion of HNMT on a diagnostic panel (added to watchlist).Created: 30 Jul 2020, 8:24 a.m. | Last Modified: 30 Jul 2020, 8:24 a.m.
Panel Version: 3.207
Heidari et al. 2015 (PMID: 26206890) described seven affected individuals from two unrelated Turkish and Kurdish consanguineous families presenting with nonsyndromic mild-profound ID (1 mild, 1 moderate, 3 severe, 2 severe-profound). Homozygous missense variants (c.179G>A; p.Gly60Asp) and (c.632T>C; p.Leu208Pro) were identified which segregated with the phenotype in each family. Functional data was supportive of defects in HNMT function.Created: 30 Jul 2020, 8:21 a.m. | Last Modified: 30 Jul 2020, 8:21 a.m.
Panel Version: 3.206
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Intellectual disability; Mental retardation, 616739
Publications
Green List (high evidence)
7 individuals from two unrelated families, some functional evidence and other circumstantial evidence linking this gene to brain function. Borderline Amber/Green.
Sources: Expert listCreated: 7 Feb 2020, 2:31 a.m.
Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal
Phenotypes
Mental retardation, autosomal recessive 51, MIM#616739
Publications
Tag Q3_21_rating was removed from gene: HNMT. Tag Q3_21_NHS_review was removed from gene: HNMT.
Source Expert Review Green was added to HNMT. Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Phenotypes for gene: HNMT were changed from Mental retardation, autosomal recessive 51, MIM#616739 to Mental retardation, autosomal recessive 51, OMIM:616739
Tag watchlist was removed from gene: HNMT. Tag Q3_21_rating tag was added to gene: HNMT. Tag Q3_21_NHS_review tag was added to gene: HNMT.
Publications for gene: HNMT were set to 26206890; 30744146
Gene: hnmt has been classified as Amber List (Moderate Evidence).
Tag watchlist tag was added to gene: HNMT.
gene: HNMT was added gene: HNMT was added to Intellectual disability. Sources: Expert list Mode of inheritance for gene: HNMT was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: HNMT were set to 26206890; 30744146 Phenotypes for gene: HNMT were set to Mental retardation, autosomal recessive 51, MIM#616739 Review for gene: HNMT was set to GREEN
If promoting or demoting a gene, please provide comments to justify a decision to move it.
Genes included in a Genomics England gene panel for a rare disease category (green list) should fit the criteria A-E outlined below.
These guidelines were developed as a combination of the ClinGen DEFINITIVE evidence for a causal role of the gene in the disease(a), and the Developmental Disorder Genotype-Phenotype (DDG2P) CONFIRMED DD Gene evidence level(b) (please see the original references provided below for full details). These help provide a guideline for expert reviewers when assessing whether a gene should be on the green or the red list of a panel.
A. There are plausible disease-causing mutations(i) within, affecting or encompassing an interpretable functional region(ii) of this gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
B. There are plausible disease-causing mutations(i) within, affecting or encompassing cis-regulatory elements convincingly affecting the expression of a single gene identified in multiple (>3) unrelated cases/families with the phenotype(iii).
OR
C. As definitions A or B but in 2 or 3 unrelated cases/families with the phenotype, with the addition of convincing bioinformatic or functional evidence of causation e.g. known inborn error of metabolism with mutation in orthologous gene which is known to have the relevant deficient enzymatic activity in other species; existence of an animal model which recapitulates the human phenotype.
AND
D. Evidence indicates that disease-causing mutations follow a Mendelian pattern of causation appropriate for reporting in a diagnostic setting(iv).
AND
E. No convincing evidence exists or has emerged that contradicts the role of the gene in the specified phenotype.
(i)Plausible disease-causing mutations: Recurrent de novo mutations convincingly affecting gene function. Rare, fully-penetrant mutations - relevant genotype never, or very rarely, seen in controls. (ii) Interpretable functional region: ORF in protein coding genes miRNA stem or loop. (iii) Phenotype: the rare disease category, as described in the eligibility statement. (iv) Intermediate penetrance genes should not be included.
It’s assumed that loss-of-function variants in this gene can cause the disease/phenotype unless an exception to this rule is known. We would like to collect information regarding exceptions. An example exception is the PCSK9 gene, where loss-of-function variants are not relevant for a hypercholesterolemia phenotype as they are associated with increased LDL-cholesterol uptake via LDLR (PMID: 25911073).
If a curated set of known-pathogenic variants is available for this gene-phenotype, please contact us at [email protected]
We classify loss-of-function variants as those with the following Sequence Ontology (SO) terms:
Term descriptions can be found on the PanelApp homepage and Ensembl.
If you are submitting this evaluation on behalf of a clinical laboratory please indicate whether you report variants in this gene as part of your current diagnostic practice by checking the box
Standardised terms were used to represent the gene-disease mode of inheritance, and were mapped to commonly used terms from the different sources. Below each of the terms is described, along with the equivalent commonly-used terms.
A variant on one allele of this gene can cause the disease, and imprinting has not been implicated.
A variant on the paternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on the maternally-inherited allele of this gene can cause the disease, if the alternate allele is imprinted (function muted).
A variant on one allele of this gene can cause the disease. This is the default used for autosomal dominant mode of inheritance where no knowledge of the imprinting status of the gene required to cause the disease is known. Mapped to the following commonly used terms from different sources: autosomal dominant, dominant, AD, DOMINANT.
A variant on both alleles of this gene is required to cause the disease. Mapped to the following commonly used terms from different sources: autosomal recessive, recessive, AR, RECESSIVE.
The disease can be caused by a variant on one or both alleles of this gene. Mapped to the following commonly used terms from different sources: autosomal recessive or autosomal dominant, recessive or dominant, AR/AD, AD/AR, DOMINANT/RECESSIVE, RECESSIVE/DOMINANT.
A variant on one allele of this gene can cause the disease, however a variant on both alleles of this gene can result in a more severe form of the disease/phenotype.
A variant in this gene can cause the disease in males as they have one X-chromosome allele, whereas a variant on both X-chromosome alleles is required to cause the disease in females. Mapped to the following commonly used term from different sources: X-linked recessive.
A variant in this gene can cause the disease in males as they have one X-chromosome allele. A variant on one allele of this gene may also cause the disease in females, though the disease/phenotype may be less severe and may have a later-onset than is seen in males. X-linked inactivation and mosaicism in different tissues complicate whether a female presents with the disease, and can change over their lifetime. This term is the default setting used for X-linked genes, where it is not known definitately whether females require a variant on each allele of this gene in order to be affected. Mapped to the following commonly used terms from different sources: X-linked dominant, x-linked, X-LINKED, X-linked.
The gene is in the mitochondrial genome and variants within this can cause this disease, maternally inherited. Mapped to the following commonly used term from different sources: Mitochondrial.
Mapped to the following commonly used terms from different sources: Unknown, NA, information not provided.
For example, if the mode of inheritance is digenic, please indicate this in the comments and which other gene is involved.