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30 Oct 2024	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.
06 May 2019	Skeletal dysplasia v1.153	CASR	Eleanor Williams Added phenotypes Hypocalcemia, autosomal dominant 601198; Hypocalciuric hypercalcemia, type I 145980; Hyperparathyroidism, neonatal 239200; Hypocalcemia, autosomal dominant, with Bartter syndrome 601198 for gene: CASR
06 Mar 2019	Skeletal dysplasia v1.147	CASR	Tracy Lester reviewed gene: CASR: Rating: GREEN; Mode of pathogenicity: ; Publications: ; Phenotypes: Hyperparathyroidism, neonatal 239200, Hypocalcemia, autosomal dominant 601198, Hypocalcemia, autosomal dominant, with Bartter syndrome 601198, Hypocalciuric hypercalcemia, type I 145980; Mode of inheritance: BOTH monoallelic and biallelic, autosomal or pseudoautosomal
06 Mar 2019	Skeletal dysplasia v1.146	CASR	Eleanor Williams reviewed gene: CASR: Rating: AMBER; Mode of pathogenicity: ; Publications: ; Phenotypes: ; Mode of inheritance:
06 Mar 2019	Skeletal dysplasia v1.145	CASR	Eleanor Williams Source NHS GMS was added to CASR. Rating Changed from Green List (high evidence) to Green List (high evidence)