rs121912855
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM5PP2PP3_ModeratePP5_Very_Strong
The NM_000094.4(COL7A1):c.6205C>T(p.Arg2069Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000254 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R2069H) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000094.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.6205C>T | p.Arg2069Cys | missense_variant | 75/119 | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.6205C>T | p.Arg2069Cys | missense_variant | 75/119 | NM_000094.4 | P1 | ||
COL7A1 | ENST00000328333.12 | c.6205C>T | p.Arg2069Cys | missense_variant | 74/118 | 1 | P1 | ||
COL7A1 | ENST00000487017.5 | n.2122C>T | non_coding_transcript_exon_variant | 40/83 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251386Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135898
GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461766Hom.: 0 Cov.: 35 AF XY: 0.0000344 AC XY: 25AN XY: 727172
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
Recessive dystrophic epidermolysis bullosa Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Center for Research in Genodermatoses and Epidermolysis Bullosa, University of Buenos Aires | Mar 14, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | 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 . - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 18, 2023 | 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). 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 not expected to disrupt COL7A1 protein function with a negative predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 27, 2022 | 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, 34674926, 22266148, 34826142, 19665875, 12787275) - |
Epidermolysis bullosa dystrophica inversa, autosomal recessive Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2003 | - - |
Recessive dystrophic epidermolysis bullosa;C0268371:Dominant dystrophic epidermolysis bullosa with absence of skin;C0432321:Pretibial dystrophic epidermolysis bullosa;C0432322:Generalized dominant dystrophic epidermolysis bullosa;C1275114:Epidermolysis bullosa pruriginosa;C1843761:Nonsyndromic congenital nail disorder 8;C1851573:Transient bullous dermolysis of the newborn Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Nov 11, 2021 | - - |
Epidermolysis bullosa dystrophica Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Biomedical Innovation Departament, CIEMAT | Jan 07, 2016 | - - |
Epidermolysis bullosa pruriginosa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PP1-M,PP4. - |
Scarring;C0162834:Hyperpigmentation of the skin;C0221260:Nail dystrophy;C0262444:Abnormality of the dentition;C0349588:Short stature;C0427065:Distal muscle weakness;C0476403:EMG abnormality;C0574769:Alopecia of scalp;C2132198:Abnormal blistering of the skin;C2315100:Failure to thrive;C3806301:Scarring alopecia of scalp;C4021800:Abnormal dental enamel morphology;C4551563:Microcephaly;C5574742:Decreased body weight Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | May 07, 2015 | - - |
Abnormal blistering of the skin Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
COL7A1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 21, 2023 | 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. - |
Generalized dominant dystrophic epidermolysis bullosa Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Centogene AG - the Rare Disease Company | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at