rs142851023

Positions:

chr2-237340907-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_004369.4(COL6A3):c.8009C>T(p.Ala2670Val) variant causes a missense change. The variant allele was found at a frequency of 0.000658 in 1,613,318 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2670T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00061 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 1 hom. )

Consequence

COL6A3
NM_004369.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:3

Conservation

PhyloP100: 5.67

Variant links:

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11057228).

BP6

Variant 2-237340907-G-A is Benign according to our data. Variant chr2-237340907-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 128822.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL6A3	NM_004369.4 linkuse as main transcript	c.8009C>T	p.Ala2670Val	missense_variant	38/44	ENST00000295550.9
COL6A3	NM_057167.4 linkuse as main transcript	c.7391C>T	p.Ala2464Val	missense_variant	37/43
COL6A3	NM_057166.5 linkuse as main transcript	c.6188C>T	p.Ala2063Val	missense_variant	35/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9 linkuse as main transcript	c.8009C>T	p.Ala2670Val	missense_variant	38/44	1	NM_004369.4	P1	P12111-1

Frequencies

GnomAD3 genomes

AF:

0.000605

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000647

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000622

AC:

156

AN:

250794

Hom.:

AF XY:

0.000657

AC XY:

AN XY:

135512

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000761

Gnomad SAS exome

AF:

0.000328

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000697

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000663

AC:

968

AN:

1461016

Hom.:

Cov.:

AF XY:

0.000652

AC XY:

474

AN XY:

726666

show subpopulations

Gnomad4 AFR exome

AF:

0.000598

Gnomad4 AMR exome

AF:

0.00105

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000605

Gnomad4 SAS exome

AF:

0.000151

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000726

Gnomad4 OTH exome

AF:

0.000663

GnomAD4 genome

AF:

0.000611

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000886

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.000313

Gnomad4 AMR

AF:

0.00189

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000647

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000661

Hom.:

Bravo

AF:

0.000827

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000601

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00107

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 23, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	COL6A3: BP4 -

Bethlem myopathy 1A

Benign:2

Benign, no assertion criteria provided	clinical testing	Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre	Jan 15, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 04, 2024

Variant summary: COL6A3 c.8009C>T (p.Ala2670Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 250794 control chromosomes (gnomAD). c.8009C>T has been reported in the literature in individuals affected with neuromuscular disorders without strong evidence of causality (e.g. Ankala_2015, Nallamilli_2018, Meinlke_2020, Marinella_2022). These reports do not provide unequivocal conclusions about association of the variant with Ullrich Congenital Muscular Dystrophy 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 25380242, 30564623, 31862442, 36498898). ClinVar contains an entry for this variant (Variation ID: 128822). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

COL6A3-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 29, 2023

The COL6A3 c.8009C>T variant is predicted to result in the amino acid substitution p.Ala2670Val. This variant has been reported in multiple patients with muscular disorders; however the pathogenicity of this change has not been elucidated with functional or segregation studies (Ankala et al. 2015. PubMed ID: 25380242; Nallamilli et al. 2018. PubMed ID: 30564623; Meinke et al. 2019. PubMed ID: 31862442; Kars et al. 2021. PubMed ID: 34426522). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD and 174 total heterozygotes. This is a higher frequency than other known pathogenic variants in the COL6A3 gene. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.72

DEOGEN2

Benign

0.36

.;T;.;T;.

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.89

D;D;D;D;.

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.11

T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Pathogenic

3.1

.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.2

N;N;N;.;N

REVEL

Pathogenic

0.73

Sift

Uncertain

0.0070

D;D;D;.;D

Sift4G

Pathogenic

0.0

D;D;D;D;D

Polyphen

0.97

D;D;.;.;D

Vest4

0.65

MVP

0.50

MPC

0.15

ClinPred

0.11

GERP RS

4.3

Varity_R

0.12

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over