rs764556767

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_001848.3(COL6A1):c.1603G>A(p.Gly535Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,460,944 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).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 1.31

Publications

2 publications found

Variant links:

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]

COL6A1 Gene-Disease associations (from GenCC):

collagen 6-related myopathy
Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
Bethlem myopathy 1A
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
Ullrich congenital muscular dystrophy 1A
Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
Bethlem myopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ullrich congenital muscular dystrophy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL6A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 21-45998425-G-A is Pathogenic according to our data. Variant chr21-45998425-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283692.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3 link	c.1603G>A	p.Gly535Arg	missense_variant	Exon 24 of 35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 link	c.1603G>A	p.Gly535Arg	missense_variant	Exon 24 of 35	1	NM_001848.3	ENSP00000355180.3
COL6A1	ENST00000683550.1 link	n.378G>A		non_coding_transcript_exon_variant	Exon 5 of 5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250686

AF XY:

0.00000737

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1460944

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726790

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000989

AC:

AN:

1111978

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Sep 18, 2024

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Replaces the glycine in the canonical Gly-X-Y repeat of the triple helical domain and is expected to disrupt normal protein folding and function, which is an established mechanism of disease (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Nov 16, 2017

Eurofins Ntd Llc (ga)

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:1

Nov 21, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL6A1 c.1603G>A (p.Gly535Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 250686 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1603G>A in individuals affected with Collagen Type VI-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. Alterations of glycine residues within the collagen triple-helix are common mechanisms of disease, however evidence for critical amino acid of this variant is insufficient. Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=2; Like pathogenic, n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Collagen 6-related myopathy

Uncertain:1

Mar 02, 2021

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL6A1 c.1603G>A (p.Gly535Arg) variant is a missense variant. A literature search was performed for the gene, cDNA change and amino acid change. No publications were found based on this search. The variant is reported at a frequency of 0.000009 in the European (non-Finnish) population from the Genome Aggregation Database, though this is based on one allele in a region of good sequencing coverage so the variant is presumed to be rare. The p.Gly535Arg variant is a glycine substitution in the triple helix domain of collagen VI. Glycine residues within the Gly-X-Y repeats of the triple helix domain are required for the structure and stability of fibrillar collagens, and glycine substitutions in this domain are the most commonly identified mutations in the collagen VI myopathies (Shoulders et al. 2009; Butterfield et al. 2013). Based on the limited evidence, the p.Gly535Arg variant is classified as a variant of uncertain significance for collagen type VI-related disorders. -

Bethlem myopathy 1A

Uncertain:1

Dec 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is present in population databases (rs764556767, gnomAD 0.0009%). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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). 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. ClinVar contains an entry for this variant (Variation ID: 283692). This variant has not been reported in the literature in individuals affected with COL6A1-related conditions. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 535 of the COL6A1 protein (p.Gly535Arg). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.97

D;T

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.9

H;.

PhyloP100

1.3

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.5

D;.

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0010

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.82

MutPred

0.82

Gain of methylation at G535 (P = 0.0285);Gain of methylation at G535 (P = 0.0285);

MVP

0.99

MPC

0.90

ClinPred

1.0

GERP RS

4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.99

Mutation Taster

=52/48

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over