Submissions for variant NM_000094.4(COL7A1):c.6206G>A (p.Arg2069His)

gnomAD frequency: 0.00005  dbSNP: rs773938350

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002009161	SCV002277360	uncertain significance	not provided	2024-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 2069 of the COL7A1 protein (p.Arg2069His). This variant is present in population databases (rs773938350, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with COL7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1488426). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL7A1 protein function with a negative predictive value of 95%. This variant disrupts the p.Arg2069 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12787275, 22266148, 28830826). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV005238146	SCV005885746	uncertain significance	not specified	2025-02-10	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.6206G>A (p.Arg2069His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 251388 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.6206G>A in individuals affected with Dystrophic Epidermolysis Bullosa, Recessive and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting the same codon has been classified as pathogenic by our lab (c.6205C>T,p.Arg2069Cys), supporting the critical relevance of codon 2069 to COL7A1 protein function. ClinVar contains an entry for this variant (Variation ID: 1488426). Based on the evidence outlined above, the variant was classified as uncertain significance.