Submissions for variant NM_000094.4(COL7A1):c.1348C>T (p.Arg450Cys)

gnomAD frequency: 0.00026  dbSNP: rs139434755

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000293523	SCV000445147	uncertain significance	Epidermolysis bullosa dystrophica	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001529118	SCV002302019	likely benign	not provided	2024-09-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155167	SCV003844748	uncertain significance	not specified	2023-02-15	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.1348C>T (p.Arg450Cys) results in a non-conservative amino acid change located in the 3rd fibronectin type III repeat (IPR003961) of 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 0.00028 (i.e. in 70 carriers) in 251298 control chromosomes (gnomAD). The high occurrence in heterozygotes makes the variant unlikely to be associated with a dominant disease, but cannot rule out the association with Recessive Dystrophic Epidermolysis Bullosa. To our knowledge, no occurrence of c.1348C>T in individuals affected with Dystrophic Epidermolysis Bullosa, and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001529118	SCV001742035	uncertain significance	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV001529118	SCV001808460	uncertain significance	not provided		no assertion criteria provided	clinical testing