rs121912938
Variant summary
Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1PM1PM2PP3_StrongPP5_Very_Strong
The NM_001848.3(COL6A1):c.850G>A(p.Gly284Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd.
Frequency
Consequence
NM_001848.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.850G>A | p.Gly284Arg | missense_variant | 9/35 | ENST00000361866.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A1 | ENST00000361866.8 | c.850G>A | p.Gly284Arg | missense_variant | 9/35 | 1 | NM_001848.3 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:7
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 20, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 05, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 15, 2021 | Immunostaining of muscle biopsies in individuals who were heterozygous for this sequence change revealed sarcolemma-specific collagen VI deficiency (Kawahara et al., 2007); Located in a region intolerant to change (Glycine within the Gly-X-Y motif in the triple helical (TH) domain ); This variant is associated with the following publications: (PMID: 24271325, 29406609, 15689448, 32154989, 29465610, 30894207, 31127727, 16130093, 17785674, 18362356, 17215366, 24959844, 19564581, 24038877, 28918041, 29244830, 32065942, 32528171) - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jun 09, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Sep 13, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Ullrich congenital muscular dystrophy 1A Pathogenic:3Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Feb 28, 2017 | The observed variant c.850G>A (p.Gly284Arg) is not reported in 1000 Genomes and ExAC databases. The in silico prediction of the variant is disease causing by MutationTaster2, tolerated by SIFT, and probably damaging by PolyPhen2. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Medicine Lab, University of California San Francisco | Jan 02, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 01, 2021 | PS1, PM1, PM2, PP3, PP5 - |
Pathogenic, criteria provided, single submitter | clinical testing | Genomic Research Center, Shahid Beheshti University of Medical Sciences | May 03, 2020 | - - |
ULLRICH CONGENITAL MUSCULAR DYSTROPHY 1A, AUTOSOMAL DOMINANT Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 07, 2009 | - - |
Bethlem myopathy 1A Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 16, 2023 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 284 of the COL6A1 protein (p.Gly284Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant Ullrich congenital muscular dystrophy (UCMD) (PMID: 15689448, 16130093, 18825676, 19564581, 24038877, 24801232). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 17180). 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 COL6A1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects COL6A1 function (PMID: 17785674). This variant disrupts the triple helix domain of COL6A1. 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). In COL6A1, variants at these glycine residues are significantly enriched in individuals with autosomal dominant disease (PMID: 15689448, 24038877) compared to the general population (ExAC). For these reasons, this variant has been classified as Pathogenic. - |
Collagen 6-related myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 21, 2023 | The COL6A1 c.850G>A (p.Gly284Arg) variant is a missense variant. Across a selection of the available literature, this variant has been identified in a heterozygous state in a total of 23 individuals with collagen 6-related myopathy encompassing a range of severity from early onset severe Ulrich congenital muscular dystrophy to the milder presentation of Bethlam myopathy (PMID: 24038877; 32154989; 34167565; 15689448). The variant occurred de novo in at least eight of these affected individuals. This variant is not found in version 2.1.1 or version 3.1.2 of the Genome Aggregation Database. The p.Gly284Arg variant lies within the triple helix domain disrupting a highly conserved Gly-Xaa-Yaa repeat motif (PMID: 20301676; 24038877). Multiple lines of computational evidence suggest the variant may impact the gene or gene product. Based on the collective evidence the c.850G>A (p.Gly284Arg) variant is classified as pathogenic for collagen 6-related myopathy. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at