rs267606750

Positions:

• chr21-46125509-G-A
• chr21-46125509-G-C

Variant summary

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

The ENST00000300527.9(COL6A2):​c.1861G>A​(p.Asp621Asn) 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D621H) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 ENST00000300527.9 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.55

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]

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 chr21-46125509-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1067448.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 21-46125509-G-A is Pathogenic according to our data. Variant chr21-46125509-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17159.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46125509-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1861G>A	p.Asp621Asn	missense_variant	25/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1861G>A	p.Asp621Asn	missense_variant	25/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1861G>A	p.Asp621Asn	missense_variant	25/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1861G>A	p.Asp621Asn	missense_variant	25/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1861G>A	p.Asp621Asn	missense_variant	25/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1861G>A	p.Asp621Asn	missense_variant	24/27	5		ENSP00000387115
COL6A2	ENST00000413758.1	c.532G>A	p.Asp178Asn	missense_variant	10/11	3		ENSP00000395751

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000322 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 05, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 24, 2017	- -

Bethlem myopathy 1A Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 04, 2023	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 621 of the COL6A2 protein (p.Asp621Asn). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal dominant limb-girdle muscular dystrophy and/or Bethlem myopathy (PMID: 11865138, 20576434). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asp620Asn. ClinVar contains an entry for this variant (Variation ID: 17159). 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 COL6A2 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Dec 21, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Bethlem myopathy 1 (MIM#158810), Ullrich congenital muscular dystrophy 1 (MIM#254090) and Myosclerosis, congenital (MIM#255600). Dominant negative is associated with pathogenic missense variants affecting the Gly-X-Y repeats within the triple helical domain while loss of function is reported for null and missense variants (DECIPHER, PMID: 19884007, 31471117) . (I) 0108 - This gene is associated with both recessive and dominant disease. (OMIM). (I) 0115 - Variants in this gene are known to have variable expressivity. The severity of collagen VI-related dystrophies manifestations may vary among family members who are heterozygous for the same pathogenic variant. (GeneReviews). (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to asparagine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools. (SP) 0600 - Variant is located in the annotated von Willebrand factor type A domain (DECIPHER). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. ClinVar contains four pathogenic/likely pathogenic entries, and three families with multiple individuals affected with Bethlem myopathy have been reported in the literature (PMID: 25535305, 32419263). (SP) 0901 - This variant has strong evidence for segregation with disease in two families (PMID: 25535305). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Bethlem myopathy 1B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 26, 2002

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.77	D;.;.;.;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;.;D;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;H;H;H;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Pathogenic	0.95
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;D;D;.
Vest4		0.94
MutPred		0.95		Gain of catalytic residue at S625 (P = 0.2208);Gain of catalytic residue at S625 (P = 0.2208);Gain of catalytic residue at S625 (P = 0.2208);Gain of catalytic residue at S625 (P = 0.2208);.;
MVP		0.97
MPC		0.60
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.95
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs267606750; hg19: chr21-47545423;