rs121912828
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_ModeratePP5_Moderate
The NM_000094.4(COL7A1):c.8393T>A(p.Met2798Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,074 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M2798I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000094.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL7A1 | NM_000094.4 | c.8393T>A | p.Met2798Lys | missense_variant | 114/119 | ENST00000681320.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL7A1 | ENST00000681320.1 | c.8393T>A | p.Met2798Lys | missense_variant | 114/119 | NM_000094.4 | P1 | ||
COL7A1 | ENST00000328333.12 | c.8393T>A | p.Met2798Lys | missense_variant | 113/118 | 1 | P1 | ||
COL7A1 | ENST00000487017.5 | n.5032T>A | non_coding_transcript_exon_variant | 78/83 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 33
GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74290
ClinVar
Submissions by phenotype
Recessive dystrophic epidermolysis bullosa Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 1993 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 17, 2023 | This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 2798 of the COL7A1 protein (p.Met2798Lys). This missense change has been observed in individual(s) with autosomal recessive dystrophic epidermolysis bullosa (PMID: 8513326). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17423). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL7A1 protein function. This variant disrupts the p.Met2798 amino acid residue in COL7A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 34435747). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at