Submissions for variant NM_000094.4(COL7A1):c.8371C>T (p.Arg2791Trp)

gnomAD frequency: 0.00109  dbSNP: rs142566193

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623488	SCV000740972	uncertain significance	Inborn genetic diseases	2015-09-01	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001148693	SCV001309601	uncertain significance	Epidermolysis bullosa dystrophica	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001358200	SCV003263173	benign	not provided	2025-01-24	criteria provided, single submitter	clinical testing
HUSP Clinical Genetics Laboratory, Hospital Universitario San Pedro De Logroño (HUSP)	RCV000193478	SCV004024232	pathogenic	Recessive dystrophic epidermolysis bullosa		criteria provided, single submitter	clinical testing
Knight Diagnostic Laboratories, Oregon Health and Sciences University	RCV000193478	SCV000223923	likely pathogenic	Recessive dystrophic epidermolysis bullosa	2014-10-13	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001275762	SCV001461234	uncertain significance	Epidermolysis bullosa dystrophica inversa, autosomal recessive	2020-09-16	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001358200	SCV001553873	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL7A1 p.Arg2791Trp variant was identified in the literature as a compound heterozygous variant in 1 of 14 patients with dystrophic epidermolysis bullosa (Dang_2007_PMID:17425959). The variant was also identified as a compound heterozygous variant in a 62 year old man with dystrophic epidermolysis bullosa who also carried a p.Gly1281Valfs*44 variant (Mahto_2013_PMID:23786535). The variant was identified in dbSNP (ID: rs142566193), ClinVar (classified as likely pathogenic by Knight Diagnostic Laboratories,Oregon Health and Sciences University, and as uncertain significance by Ambry Genetics) and LOVD 3.0 (classified as pathogenic, likely pathogenic and VUS). The variant was identified in control databases in 284 of 262690 chromosomes (2 homozygous) at a frequency of 0.001081 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 213 of 120204 chromosomes (freq: 0.001772), Other in 8 of 6758 chromosomes (freq: 0.001184), European (Finnish) in 22 of 23032 chromosomes (freq: 0.000955), African in 14 of 23204 chromosomes (freq: 0.000603), Latino in 16 of 32778 chromosomes (freq: 0.000488) and South Asian in 11 of 28376 chromosomes (freq: 0.000388), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.Arg2791 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003907713	SCV004718092	likely benign	COL7A1-related disorder	2024-05-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).