rs121912938

chr21-45989129-G-A

Variant summary

Our verdict is Pathogenic. Variant got 20 ACMG points: 20P and 0B. PS1 PM1 PM2 PP3_Strong PP5_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: Genomes: not found (cov: 33)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:13 U:1
• Conservation: PhyloP100: 8.56

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 20 ACMG points.

• PS1: Transcript NM_001848.3 (COL6A1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in NM_001848.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-45989129-G-A is Pathogenic according to our data. Variant chr21-45989129-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45989129-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-45989129-G-A is described in Lovd as [Pathogenic]. Variant chr21-45989129-G-A is described in Lovd as [Pathogenic].

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

Significance: Pathogenic

Submissions summary: Pathogenic:13 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 09, 2017	- -
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, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Ullrich congenital muscular dystrophy 1A Pathogenic:3 Uncertain:1

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 -
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 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D;D
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.4	H;.
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.7	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.99
MutPred		0.99		Loss of methylation at K280 (P = 0.0681);Loss of methylation at K280 (P = 0.0681);
MVP		1.0
MPC		0.26
ClinPred		1.0	D
GERP RS		3.6
Varity_R		0.92
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs121912938; hg19: chr21-47409043; COSMIC: COSV62612600; COSMIC: COSV62612600;