Submissions for variant NM_000094.4(COL7A1):c.5314C>T (p.Arg1772Trp)

gnomAD frequency: 0.00001  dbSNP: rs1032335328

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000778703	SCV000915056	likely pathogenic	Epidermolysis bullosa dystrophica	2018-10-31	criteria provided, single submitter	clinical testing	The COL7A1 c.5314C>T (p.Arg1772Trp) variant is a missense variant that has been reported in three studies and identified in six individuals with dystrophic epidermolysis bullosa, including in a homozygous state in five individuals and in a compound heterozygous state with a frameshift variant in one individual (Whittock et al. 1999; Takeichi et al. 2013; Shah et al. 2017). The five homozygotes comprised two sets of siblings from consanguineous families (Takeichi et al. 2013; Shah et al. 2017). The p.Arg1772Trp variant was absent from 195 controls and is reported at a frequency of 0.000032 in the South Asian population of the Genome Aggregation Database. This frequency is based on one allele in a region of good sequencing coverage; therefore, the variant is presumed to be rare. Based on the evidence, the p.Arg1772Trp variant is classified as likely pathogenic for dystrophic epidermolysis bullosa. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001856162	SCV002243890	pathogenic	not provided	2024-08-02	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 1772 of the COL7A1 protein (p.Arg1772Trp). This variant is present in population databases (no rsID available, gnomAD 0.003%). This missense change has been observed in individuals with autosomal recessive dystrophic epidermolysis bullosa (PMID: 10504458, 24279917, 29130490). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 631924). 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 COL7A1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
3billion, Medical Genetics	RCV002051892	SCV002318753	pathogenic	Recessive dystrophic epidermolysis bullosa	2022-03-22	criteria provided, single submitter	clinical testing	Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000631924, PMID:10504458). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals(PMID: 29130490, 24279917, 10504458). In silico tool predictions suggest damaging effect of the variant on gene or gene product(REVEL: 0.749>=0.6). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
GeneDx	RCV001856162	SCV002817698	pathogenic	not provided	2024-04-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24279917, 29130490, Jan[thesis]2016, 10504458, 36287101)
Fulgent Genetics, Fulgent Genetics	RCV005036099	SCV005664194	pathogenic	Recessive dystrophic epidermolysis bullosa; Pretibial dystrophic epidermolysis bullosa; Dominant dystrophic epidermolysis bullosa with absence of skin; Transient bullous dermolysis of the newborn; Epidermolysis bullosa pruriginosa; Nonsyndromic congenital nail disorder 8; Generalized dominant dystrophic epidermolysis bullosa	2024-04-06	criteria provided, single submitter	clinical testing
University of Washington Center for Mendelian Genomics, University of Washington	RCV000778703	SCV001479769	likely pathogenic	Epidermolysis bullosa dystrophica		no assertion criteria provided	research