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Skeletal dysplasia v7.23 TOMM7 Achchuthan Shanmugasundram Tag Q3_24_promote_green was removed from gene: TOMM7.
Tag Q3_24_NHS_review was removed from gene: TOMM7.
Skeletal dysplasia v7.23 TOMM7 Achchuthan Shanmugasundram reviewed gene: TOMM7: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance: BIALLELIC, autosomal or pseudoautosomal
Skeletal dysplasia v7.22 TOMM7 Achchuthan Shanmugasundram Source NHS GMS was added to TOMM7.
Source Expert Review Green was added to TOMM7.
Rating Changed from Amber List (moderate evidence) to Green List (high evidence)
Skeletal dysplasia v7.4 TOMM7 Eleanor Williams Publications for gene: TOMM7 were set to PMID: 36282599; PMID: 36299998
Skeletal dysplasia v7.3 TOMM7 Eleanor Williams Phenotypes for gene: TOMM7 were changed from Garg-Mishra progeroid syndrome; dwarfism; mandibular hypoplasia; microphthalmia; hyperopia; partial lipodystrophy to Garg-Mishra progeroid syndrome, OMIM:620601; Garg-Mishra progeroid syndrome, MONDO:0957953
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams Deleted their comment
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams changed review comment from: Associated with Garg-Mishra progeroid syndrome, 620601 (AR) in OMIM.

As reviewer Hannah Knight states, 2 cases reported with different homozygous missense variants in TOMM7:

PMID: 36282599 - Garg et al 2022, man of Chinese ancestry with an autosomal recessive form of progeria, characterized by severe proportionate short stature with relative macrocephaly, dysmorphisms and significant learning disabilities. The variant c.86C>T; p.Pro29Leu) in TOMM7 was found in a homozygous state in the proband, while parents and unaffected siblings were heterozyous. Functional studies showed reduced interactions between the mutant protein and core TOMM complex proteins in patient fibroblasts, aswell as increased mitochondrial oxygen consumption compared to control cells

PMID: 36299998. Young et al 2022 - report a Japanese patient with a TOMM7 homozygous variant (c.73T>C, p.Trp25Arg). The proband presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Results of studies with mouse models of TOMM7 deletion and also with knockin with the same variant suggest that the missense variant causes partial loss of Tomm7 function, producing a milder but still lethal phenotype compared to deletion.

A 3rd case is reported in PMID: 39333057 Yeole et al 2024 in which a homozygous splice variant c.153-2A > C in TOMM7 (NM_019059.5) was identified. The consanguineous parents were heterozygous for this variant. 2 siblings died after 52 days and 4 months of life respectively. Exome analysis was from the older sibling. In this case the phenotype was of neonatal-onset hypotonia, lactic acidosis, optic atrophy, and neuroimaging results suggestive of Leigh disease. Additionally Additionally, a known missense variant c.186G > C p.(Arg62Ser) in exon 3 of CASR (NM_001178065.2) was identified in causing hyperparathyroidism. No skeletal examination was performed.; to: Associated with Garg-Mishra progeroid syndrome, 620601 (AR) in OMIM.

As reviewer Hannah Knight states, 2 cases reported with different homozygous missense variants in TOMM7:

PMID: 36282599 - Garg et al 2022, man of Chinese ancestry with an autosomal recessive form of progeria, characterized by severe proportionate short stature with relative macrocephaly, dysmorphisms and significant learning disabilities. The variant c.86C>T; p.Pro29Leu) in TOMM7 was found in a homozygous state in the proband, while parents and unaffected siblings were heterozyous. Functional studies showed reduced interactions between the mutant protein and core TOMM complex proteins in patient fibroblasts, aswell as increased mitochondrial oxygen consumption compared to control cells

PMID: 36299998. Young et al 2022 - report a Japanese patient with a TOMM7 homozygous variant (c.73T>C, p.Trp25Arg). The proband presented with a syndromic short stature, skeletal abnormalities, muscle hypotonia, microvesicular liver steatosis, and developmental delay. Results of studies with mouse models of TOMM7 deletion and also with knockin with the same variant suggest that the missense variant causes partial loss of Tomm7 function, producing a milder but still lethal phenotype compared to deletion. In addition, analysis of tibial growth plates in mutant mice showed shortening of the growth plate, suggesting reduced chondrocyte proliferation which could lead to the skeletal phenotype.

A 3rd case is reported in PMID: 39333057 Yeole et al 2024 in which a homozygous splice variant c.153-2A > C in TOMM7 (NM_019059.5) was identified. The consanguineous parents were heterozygous for this variant. 2 siblings died after 52 days and 4 months of life respectively. Exome analysis was from the older sibling. In this case the phenotype was of neonatal-onset hypotonia, lactic acidosis, optic atrophy, and neuroimaging results suggestive of Leigh disease. Additionally, a known missense variant c.186G > C p.(Arg62Ser) in exon 3 of CASR (NM_001178065.2) was identified in causing hyperparathyroidism. No skeletal examination was performed.
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams Classified gene: TOMM7 as Amber List (moderate evidence)
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams Added comment: Comment on list classification: 2 cases reported with a skeletal phenotype with additional functional evidence for pathogenicity for the missense variants. A 3rd case with with a homozyous splice variant reports a more severe phenotype, with no skeletal phenotype recorded but earlier death.

Recommend green rating following GMS approval.
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams Gene: tomm7 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams Classified gene: TOMM7 as Amber List (moderate evidence)
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams Added comment: Comment on list classification: 2 cases reported with a skeletal phenotype with additional functional evidence for pathogenicity for the missense variants. A 3rd case with with a homozyous splice variant reports a more severe phenotype, with no skeletal phenotype recorded but earlier death.

Recommend green rating following GMS approval.
Skeletal dysplasia v7.2 TOMM7 Eleanor Williams Gene: tomm7 has been classified as Amber List (Moderate Evidence).
Skeletal dysplasia v7.1 TOMM7 Eleanor Williams Tag Q3_24_promote_green tag was added to gene: TOMM7.
Tag Q3_24_NHS_review tag was added to gene: TOMM7.
Skeletal dysplasia v7.1 TOMM7 Eleanor Williams commented on gene: TOMM7
Skeletal dysplasia v6.23 TOMM7 Hannah Knight gene: TOMM7 was added
gene: TOMM7 was added to Skeletal dysplasia. Sources: Literature
Mode of inheritance for gene: TOMM7 was set to BIALLELIC, autosomal or pseudoautosomal
Publications for gene: TOMM7 were set to PMID: 36282599; PMID: 36299998
Phenotypes for gene: TOMM7 were set to Garg-Mishra progeroid syndrome; dwarfism; mandibular hypoplasia; microphthalmia; hyperopia; partial lipodystrophy
Review for gene: TOMM7 was set to AMBER
Added comment: PMID: 36282599 (2022) reported a homozygous missense variant in TOMM7 (P29L) in a patient with short stature, dysmorphisms, poor vision, and significant learning disabilities
PMID: 36299998 (2023) reported a homozygous missense variant in TOMM7 (W25R) in a patient with short stature and growth failure

In both cases, parents were tested and found to be heterozygous for the same variant
Sources: Literature