rs373072443

Positions:

chr21-46131980-C-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM5PP3PP5_Very_Strong

The NM_001849.4(COL6A2):c.2488C>T(p.Arg830Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,608,588 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R830Q) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

COL6A2
NM_001849.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4U:1

Conservation

PhyloP100: 3.20

Variant links:

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. 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 this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr21-46131981-G-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.771

PP5

Variant 21-46131980-C-T is Pathogenic according to our data. Variant chr21-46131980-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 287934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46131980-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4 linkuse as main transcript	c.2488C>T	p.Arg830Trp	missense_variant	28/28	ENST00000300527.9	NP_001840.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9 linkuse as main transcript	c.2488C>T	p.Arg830Trp	missense_variant	28/28	1	NM_001849.4	ENSP00000300527	P1	P12110-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000339

AC:

AN:

236068

Hom.:

AF XY:

0.0000309

AC XY:

AN XY:

129444

show subpopulations

Gnomad AFR exome

AF:

0.0000674

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000563

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000572

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000385

AC:

AN:

1456250

Hom.:

Cov.:

AF XY:

0.0000387

AC XY:

AN XY:

724448

show subpopulations

Gnomad4 AFR exome

AF:

0.0000599

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000200

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000118

Hom.:

Bravo

AF:

0.0000264

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:1

Uncertain significance, flagged submission	clinical testing	Eurofins Ntd Llc (ga)	May 04, 2016	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 09, 2023	- -

Bethlem myopathy 1A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg830 amino acid residue in COL6A2. Other variant(s) that disrupt this residue have been observed in individuals with COL6A2-related conditions (PMID: 29419890), which suggests that this may be a clinically significant amino acid residue. 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 not expected to disrupt COL6A2 protein function. ClinVar contains an entry for this variant (Variation ID: 287934). This missense change has been observed in individual(s) with autosomal recessive Bethlem myopathy and/or limb-girdle muscular dystrophy (PMID: 19884007, 30564623, 31127727, 34167565). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 830 of the COL6A2 protein (p.Arg830Trp). -

Collagen 6-related myopathy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

May 09, 2017

The COL6A2 c.2488C>T (p.Arg830Trp) missense variant has been reported in two studies and is found in a compound heterozygous state in a total of three individuals, including two siblings with recessive Bethlem myopathy and an unrelated individual with a recessive limb-girdle muscular dystrophy phenotype (Foley et al. 2009; Mitsui et al. 2016). The variant was also identified in a heterozygous state in the unaffected father of the siblings. Control data are unavailable for this variant, which is reported at a frequency of 0.00004 in the Total population of the Exome Aggregation Consortium. Foley et al. (2009) performed collagen VI staining using dermal fibroblasts from one of the siblings and found that collagen VI was deposited but differed in appearance and amount compared to collagen VI deposited by normal fibroblasts. Based on the evidence, the p.Arg830Trp variant is classified as likely pathogenic for recessive collagen type VI-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Ullrich congenital muscular dystrophy 1A

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Neuberg Centre For Genomic Medicine, NCGM

The missense variant c.2488C>T (p.Arg830Trp) in COL6A2 gene has been reported in two studies and is found in a compound heterozygous state in a total of three individuals, including two siblings with recessive Bethlem myopathy and an unrelated individual with a recessive limb-girdle muscular dystrophy phenotype (Foley et al. 2009). This variant has been reported to the ClinVar database with conflicting interpretations of Uncertain Significance/Likely Pathogenic. The variant p.Arg830Trp is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.003365% is reported in gnomAD. The amino acid Arg at position 830 is changed to a Trp changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Arg830Trp in COL6A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Likely Pathogenic. The observed variation is present in the father in a heterozygous state. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.64

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

1.9

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-3.0

REVEL

Pathogenic

0.69

Sift

Uncertain

0.016

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.66

MVP

0.87

MPC

0.62

ClinPred

0.67

GERP RS

4.2

Varity_R

0.22

gMVP

0.80

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

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