ClinVar Miner

Submissions for variant NM_000359.3(TGM1):c.790C>T (p.Arg264Trp)

gnomAD frequency: 0.00001  dbSNP: rs201868387
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413495 SCV000490847 pathogenic not provided 2024-07-09 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect on enzyme activity (PMID: 19212342); This variant is associated with the following publications: (PMID: 31589614, 30693114, 19241467, 19212342, 16968736, 27025581, 34273205, 28403434, 38061711)
Counsyl RCV000673755 SCV000798993 likely pathogenic Autosomal recessive congenital ichthyosis 1 2018-04-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000413495 SCV001582771 pathogenic not provided 2023-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 264 of the TGM1 protein (p.Arg264Trp). This variant is present in population databases (rs201868387, gnomAD 0.006%). This missense change has been observed in individuals with bathing suit ichthyosis or congenital ichthyosiform erythroderma (PMID: 16968736, 27025581, 28403434). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372532). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TGM1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects TGM1 function (PMID: 19212342). For these reasons, this variant has been classified as Pathogenic.
Revvity Omics, Revvity RCV000673755 SCV002018960 pathogenic Autosomal recessive congenital ichthyosis 1 2021-05-06 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000673755 SCV002763862 likely pathogenic Autosomal recessive congenital ichthyosis 1 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV000673755 SCV003921776 pathogenic Autosomal recessive congenital ichthyosis 1 2022-09-02 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with autosomal recessive congenital ichthyosis 1 (MIM#242300). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to tryptophan. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (v2) (5 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated catalytic core domain (PMID: 28403434). (I) 0704 - Another missense variant comparable to the one identified in this case has limited previous evidence for pathogenicity. A different variant in the same codon resulting in a change to a glutamine has been previously reported in individuals with ichthyosis (ClinVar, PMID: 16968736). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in individuals with ichthyosis (ClinVar, PMID: 16968736, PMID: 28403434). (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (c.877-2A>G) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Baylor Genetics RCV000673755 SCV004203759 pathogenic Autosomal recessive congenital ichthyosis 1 2024-03-03 criteria provided, single submitter clinical testing
Natera, Inc. RCV000673755 SCV002091227 pathogenic Autosomal recessive congenital ichthyosis 1 2020-08-17 no assertion criteria provided clinical testing

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