Submissions for variant NM_000094.4(COL7A1):c.6205C>T (p.Arg2069Cys)

gnomAD frequency: 0.00001  dbSNP: rs121912855

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414882	SCV000492870	pathogenic	Short stature; Failure to thrive; Abnormality of the dentition; Microcephaly; Abnormal dental enamel morphology; Hyperpigmentation of the skin; Alopecia of scalp; Distal muscle weakness; EMG abnormality; Decreased body weight; Scarring alopecia of scalp; Abnormal blistering of the skin; Nail dystrophy; Scarring	2015-05-07	criteria provided, single submitter	clinical testing
GeneDx	RCV000498291	SCV000589318	pathogenic	not provided	2023-10-04	criteria provided, single submitter	clinical testing	Reported as heterozygous in two affected individuals without another COL7A1 variant; however, studies were not comprehensive and did not exclude other variants/molecular causes (Hamidi et al., 2016; Danescu et al., 2015); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 18558993, 32860008, 31589614, 32484238, 16484981, 20598510, 25201089, 26707537, 28830826, 27746867, 31001817, 34286919, 34308104, 22266148, 34826142, 19665875, 12787275, 34674926)
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000626608	SCV000747309	pathogenic	Abnormal blistering of the skin	2017-01-01	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000498291	SCV000958934	pathogenic	not provided	2024-10-18	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2069 of the COL7A1 protein (p.Arg2069Cys). This variant is present in population databases (rs121912855, gnomAD 0.004%). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 12787275, 22266148, 28830826). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17463). 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%. For these reasons, this variant has been classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001199071	SCV001370066	pathogenic	Epidermolysis bullosa pruriginosa	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP1-M,PP4.
Centogene AG - the Rare Disease Company	RCV001251179	SCV001426534	pathogenic	Generalized dominant dystrophic epidermolysis bullosa		criteria provided, single submitter	clinical testing
Biomedical Innovation Departament, CIEMAT	RCV001352770	SCV001547352	pathogenic	Epidermolysis bullosa dystrophica	2016-01-07	criteria provided, single submitter	research
Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires	RCV002276566	SCV002499349	pathogenic	Recessive dystrophic epidermolysis bullosa	2022-03-14	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002496411	SCV002813815	likely 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	2021-11-11	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV002276566	SCV004047109	pathogenic	Recessive dystrophic epidermolysis bullosa		criteria provided, single submitter	clinical testing	The missense variant c.6205C>T (p.Arg2069Cys) in COL7A1 gene has been observed in individual(s) with dystrophic epidermolysis bullosa (Vahidnezhad H et.al.,2017).The p.Arg2069Cys variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.00001989% is reported in gnomAD. This variant has been reported to the ClinVar database as Pathogenic. It has also been observed to segregate with disease in related individuals. The amino acid Arg at position 2069 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg2069Cys in COL7A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic .
Neuberg Centre For Genomic Medicine, NCGM	RCV001199071	SCV005373607	pathogenic	Epidermolysis bullosa pruriginosa	2023-06-02	criteria provided, single submitter	clinical testing	The observed missense variant c.6205C>T(p.Arg2069Cys) in COL7A1 gene has been reported previously in homozygous and compound heterozygous state in individual(s) with dystrophic epidermolysis bullosa (Hamidi AK, et al., 2016; Liao Y, et al., 2018; ). This variant is present in a mutational hotspot. A different amino acid change (c.6206G>A, p.Arg2069His) has been previously reported as a Likely pathogenic in the ClinVar database.This variant is reported with the allele frequency 0.002% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Pathogenic/Likely Pathogenic by multiple submitters. The amino acid Arg at position 2069 is changed to a Cys changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen - Possibly damaging, SIFT – Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. The residue is conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002276566	SCV005394474	pathogenic	Recessive dystrophic epidermolysis bullosa	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: COL7A1 c.6205C>T (p.Arg2069Cys) 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 2e-05 in 251386 control chromosomes. c.6205C>T has been reported in the literature in multiple individuals affected with autosomal recessive Dystrophic Epidermolysis Bullosa (e.g. Kahofer_2003, Chen_2023). These data indicate that the variant is very likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 12787275, 36287101). ClinVar contains an entry for this variant (Variation ID: 17463). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000019015	SCV000039302	pathogenic	Epidermolysis bullosa dystrophica inversa, autosomal recessive	2003-05-01	no assertion criteria provided	literature only
Natera, Inc.	RCV000019015	SCV001454259	pathogenic	Epidermolysis bullosa dystrophica inversa, autosomal recessive	2020-09-16	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003924844	SCV004742111	pathogenic	COL7A1-related disorder	2023-11-21	no assertion criteria provided	clinical testing	The COL7A1 c.6205C>T variant is predicted to result in the amino acid substitution p.Arg2069Cys. This variant has been reported in the compound heterozygous or homozygous state in individuals with epidermolysis bullosa dystrophica, and has been shown to segregate with disease within families (Kahofer et al. 2003. PubMed ID: 12787275; Vahidnezhad et al. 2017. PubMed ID: 28830826; Mariath et al. 2019. PubMed ID: 31001817; Ma et al. 2021. PubMed ID: 34286919). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.