chr21-45990257-G-A

Position:

• chr21-45990257-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001848.3(COL6A1):​c.931-1G>A variant causes a splice acceptor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: COL6A1 NM_001848.3 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 5.95

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.008422417 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.4, offset of 1, new splice context is: ccgcttcctgtctccgcaAGgct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-45990257-G-A is Pathogenic according to our data. Variant chr21-45990257-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 17170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45990257-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.931-1G>A		splice_acceptor_variant, intron_variant		ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.931-1G>A		splice_acceptor_variant, intron_variant		1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 16, 2023	This sequence change affects an acceptor splice site in intron 11 of the COL6A1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in COL6A1 are known to be pathogenic (PMID: 19884007, 20976770). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 9580662). Studies have shown that disruption of this splice site alters COL6A1 gene expression (PMID: 9580662). ClinVar contains an entry for this variant (Variation ID: 17170). This variant is also known as 979-1G>A. Disruption of this splice site has been observed in individual(s) with Bethlem myopathy (PMID: 9580662, 28688748). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Feb 02, 2022	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) and Ullrich congenital muscular dystrophy 1 (MIM#254090). Dominant negative is associated with pathogenic missense variants affecting the Gly-X-Y repeat within the triple helical domain while loss of function is reported for null and missense variants (DECIPHER, PMID: 20976770). (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 (GeneReviews). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This variant has been shown to result in a single nucleotide deletion, subsequent mRNA instability and nonsense-mediated decay (PMID: 9580662). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0701 - Other null variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. There are at least ten NMD-predicted variants that have been classified as pathogenic (DECIPHER, ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been classified once as pathogenic by a clinical diagnostic laboratory (ClinVar). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant has been shown to segregate in at least eight affected individuals within one family (PMID: 9580662). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 1998	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 25, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	33
DANN	Uncertain	0.99
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.96	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.96		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.35		Position offset: 2
DS_AL_spliceai		0.96		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs886042354; hg19: chr21-47410171;