rs121912838
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM5PP2PP3_StrongPP5
The NM_000094.4(COL7A1):c.6091G>A(p.Gly2031Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000932 in 1,609,700 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G2031V) 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 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.6091G>A | p.Gly2031Ser | missense_variant | 74/119 | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.6091G>A | p.Gly2031Ser | missense_variant | 74/119 | NM_000094.4 | P1 | ||
COL7A1 | ENST00000328333.12 | c.6091G>A | p.Gly2031Ser | missense_variant | 73/118 | 1 | P1 | ||
COL7A1 | ENST00000487017.5 | n.2008G>A | non_coding_transcript_exon_variant | 39/83 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000253 AC: 6AN: 237354Hom.: 0 AF XY: 0.0000307 AC XY: 4AN XY: 130280
GnomAD4 exome AF: 0.00000823 AC: 12AN: 1457548Hom.: 0 Cov.: 39 AF XY: 0.00000828 AC XY: 6AN XY: 725054
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152152Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
ClinVar
Submissions by phenotype
Recessive dystrophic epidermolysis bullosa Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2001 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 10, 2022 | Identified in multiple unrelated patients referred for genetic testing at GeneDx and in the published literature, with either an autosomal dominant or autosomal recessive inheritance pattern, sometimes presenting with different inheritance patterns in members of the same family (Almaani et al., 2011; Hamidi et al., 2016; E Pfendner, unpublished); Located in the highly conserved Gly-X-Y repeat of the collagenous domain; Glycine substitution variants in this region of the COLVII protein destabilize the collagen triple helix resulting in skin fragility due to poor anchoring of the basement membrane to the underlying dermis (Pfendner and Lucky, 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34435747, 21448560, 11167698, 27746867, 31216405, 30924923) - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 17, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 2031 of the COL7A1 protein (p.Gly2031Ser). This variant is present in population databases (rs121912838, gnomAD 0.06%). This missense change has been observed in individual(s) with autosomal recessive epidermolysis bullosa (PMID: 11167698, 27746867). ClinVar contains an entry for this variant (Variation ID: 17446). 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%. This variant disrupts the triple helix domain of COL7A1. Glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (PMID: 7695699, 8218237, 19344236), and variants at these glycine residues in COL7A1 are more frequently observed in individuals with disease than in the general population (PMID: 22058051). However, the clinical significance of this observation remains uncertain since only a limited number of affected individuals have been described to date. For these reasons, this variant has been classified as Pathogenic. - |
Epidermolysis bullosa dystrophica Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 10, 2020 | - - |
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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 20, 2012 | - - |
Duane retraction syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Feb 26, 2024 | The heterozygous p.Gly2031Ser variant in COL7A1 was identified in 1 individual with Duane Retraction Syndrome (DRS), hand and finger anomalies, and absent nails via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Engle lab (https://kirbyneuro.org/EngleLab/). While this gene has a definitive gene-disease association with autosomal dominant or recessive dystrophic epidermolysis bullosa and an autosomal dominant nail disorder, it is lacking sufficient evidence to establish a gene-disease relationship for DRS. An additional variant (p.Arg894Cys) in KIF5C was also detected in heterozygosity with this variant. While these genes are lacking sufficient evidence, we believe that both variants may be contributing to the phenotype. Given the limited information about this gene-disease relationship, the significance of the p.Gly2031Ser variant is uncertain. If you have any additional information about functional evidence or other individuals with this phenotype that also have variants in COL7A1 we encourage you to reach out to the Engle Lab (elizabeth.engle@childrens.harvard.edu). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at