21-45990792-G-T

Position:

• chr21-45990792-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_001848.3(COL6A1):​c.1022G>T​(p.Gly341Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. G341C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 4.75

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 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-45990791-G-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.994
• PP5: Variant 21-45990792-G-T is Pathogenic according to our data. Variant chr21-45990792-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 282533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45990792-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1022G>T	p.Gly341Val	missense_variant	14/35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.1022G>T	p.Gly341Val	missense_variant	14/35	1	NM_001848.3	ENSP00000355180	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 06, 2018	The G341V pathogenic variant in the COL6A1 gene has been previously reported in multiple unrelated individuals with Bethlem myopathy (Lampe et al., 2005; Lucioli et al., 2005; Deconinck et al., 2014; Ghaoui et al., 2015). Reported individuals did not have a second identifiable COL6A1 pathogenic variant, and G341V was found to be de novo in two cases (Deconinck et al., 2014; Ghaoui et al., 2015). The G341V variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs within the Gly-X-Y motif in the triple helical (TH) domain of collagen VI, a region that is well-conserved across species. Additionally, a different missense variant at the same position (G341D) has been previously reported in a family with autosomal dominant Bethlem myopathy (Scacheri et al., 2002). Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2017	- -

COL6A1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2023

The COL6A1 c.1022G>T variant is predicted to result in the amino acid substitution p.Gly341Val. This variant was reported in the heterozygous state in an an individual with Bethlem myopathy and found to segregate in two other affected family members, indicating autosomal dominant inheritance (Lucioli et al 2005. PubMed ID: 15955946). This variant has also been reported to occur de novo in a patient with limb girdle muscular dystrophy and in other patients with features of COL6A1-related disorders (See Table 3 Ghaoui R et al 2015. PubMed ID: 26436962; Deconinck N et al 2010. PubMed ID: 20576434; Table 1 Kim J et al 2011. PubMed ID: 22075033; Deconinck N et al 2014. PubMed ID: 25535305). A different substitution at this position (p.Gly341Asp) has also been reported in a family with autosomal dominant Bethlem myopathy (Scacheri PC et al 2002. PubMed ID: 11865138). This variant disrupts the triple helix domain of COL6A1 and glycine residues within the Gly-Xaa-Yaa repeats of the triple helix domain are required for the structure and stability of fibrillar collagens (Long et al. 1993. PubMed ID: 8218237; Bella et al. 1994. PubMed ID: 7695699; Shoulders et al. 2009. PubMed ID: 19344236). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic for autosomal dominant COL6A1-related disorders. -

Bethlem myopathy 1A Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 06, 2024

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 341 of the COL6A1 protein (p.Gly341Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant COL6A1-related conditions (PMID: 15689448, 15955946, 20576434, 22075033, 25535305, 26436962). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 282533). 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 95%. 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). This variant disrupts the p.Gly341 amino acid residue in COL6A1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11865138, 24038877). 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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;T
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	4.3	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-7.6	D;.
REVEL	Pathogenic	0.99
Sift	Uncertain	0.0030	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.98		Gain of catalytic residue at M337 (P = 0.0295);Gain of catalytic residue at M337 (P = 0.0295);
MVP		0.98
MPC		0.28
ClinPred		1.0	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs121912935; hg19: chr21-47410706;