ClinVar Miner

Submissions for variant NM_000093.5(COL5A1):c.2998G>A (p.Gly1000Ser)

dbSNP: rs765082093
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001192884 SCV001361320 uncertain significance not specified 2021-05-24 criteria provided, single submitter clinical testing Variant summary: COL5A1 c.2998G>A (p.Gly1000Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250942 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant c.2998G>A has been observed de novo in a whole exome sequencing case in our laboratory. To our knowledge, no other occurrence of c.2998G>A in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV002240931 SCV001397959 uncertain significance Ehlers-Danlos syndrome, classic type, 1 2019-09-12 criteria provided, single submitter clinical testing Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and missense variants at these glycine residues in COL5A1 are more frequently observed in individuals with disease than in the general population (PMID: 22696272, 23587214). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has been observed in an individual with clinical features of COL5A1-related conditions (Invitae). This variant is present in population databases (rs765082093, ExAC 0.002%). This sequence change replaces glycine with serine at codon 1000 of the COL5A1 protein (p.Gly1000Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine.

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