rs398123631

Variant names:

• chr21-45990827-G-A
• rs398123631
• NM_001848.3:c.1056+1G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45990827-G-A
• chr21-45990827-G-C
• chr21-45990827-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_001848.3(COL6A1):​c.1056+1G>A variant causes a splice donor, 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A1 NM_001848.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14 O:1
• Conservation: PhyloP100: 4.73
• Publications: 11 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.017492712 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 21-45990827-G-A is Pathogenic according to our data. Variant chr21-45990827-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.1056+1G>A		splice_donor_variant, intron_variant	Intron 14 of 34	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.1056+1G>A		splice_donor_variant, intron_variant	Intron 14 of 34	1	NM_001848.3	ENSP00000355180.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00000534 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:7

May 20, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 30, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1056+1 G>A pathogenic variant in the COL6A1 gene has been previously reported in multiple patients with COL6A1-related disorders (Lamande et al., 1999; Pan et al., 2003; Lucioli et al., 2005; Baker et al., 2007; Kawahara et al., 2008). Reported individuals did not have a second identifiable COL6A1 pathogenic variant, and c.1056+1 G>A was found to be de novo in one case (Pan et al., 2003). This variant destroys the canonical splice donor site of intron 14 and functional studies demonstrate that it results in the skipping of exon 14, leading to abnormal gene splicing (Pan et al., 2003; Baker et al., 2007). It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. -

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Clinical Genetics, Academic Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bethlem myopathy 1A Pathogenic:5 Other:1

Oct 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Common variant that results in exon 14 skipping -

Sep 27, 2023

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Canonical splice site: predicted to alter splicing and result in a loss or disruption of normal protein function. Multiple pathogenic loss-of-function variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000017174 /PMID: 10419498). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous c.1056+1G>A variant in COL6A1 was identified by our study in one individual with congenital myopathy. Trio exome analysis showed this variant to be de novo. The c.1056+1G>A variant in COL6A1 has been reported in 19 unrelated individuals with autosomal dominant COL6A1-related myopathy (PMID: 24271325, PMID: 29419890, PMID: 25749816, PMID: 15955946, PMID: 17886299, PMID: 10419498, PMID: 12840783) and segregated with disease in 18 affected relatives from six families (PMID: 25749816, PMID: 15955946). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was previously found to be de novo in three individuals with paternity and maternity confirmed (PMID: 12840783, PMID: 29419890) and was assumed de novo in one individual but maternity and paternity have not been confirmed (PMID: 15955946). This variant has also been reported in ClinVar (Variation ID: 17174) and has been interpreted as pathogenic by multiple submitters. This variant was absent from large population studies. RT-PCR analysis performed on affected tissue shows evidence of altered splicing, with in-frame skipping of exon 14 (PMID: 17886299, PMID: 10419498). Two different nucleotide changes that also result in a splice donor variant at the same site, c.1056+1G>T and c.1056+1G>C, have been previously reported pathogenic (ClinVar Variation ID: 946468, 1322138), and the variant being assessed here, c.1056+1G>A, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. There is an in-frame cryptic splice site 54 bases from the intron-exon boundary, providing evidence that this variant may delete 18 amino acids instead of causing loss of function. However, this information is not predictive enough to determine pathogenicity. Heterozygous loss of function of the COL6A1 gene is an established disease mechanism in autosomal dominant COL6A1-related myopathy. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant COL6A1-related myopathy. ACMG/AMP Criteria applied: PVS1_Moderate, PS1_Supporting, PS2, PS3_Moderate, PM2_Supporting, PM3_VeryStrong, PM6_Supporting, PP1_Strong (Richards 2015). -

Jun 21, 2022

MGZ Medical Genetics Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 14 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 disease-causing for autosomal recessive COL6A1-related conditions (PMID: 21280092, 20976770). However, certain variants affecting donor or acceptor splice sites in the triple helical domain of COL6A1 are expected to result in in-frame exon skipping and have been reported to cause autosomal dominant COL6A1-related conditions (PMID: 18366090). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with autosomal dominant Bethlem myopathy (PMID: 10419498, 12840783, 15955946, 17886299, 25749816). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17174). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (PMID: 10419498, 12840783). For these reasons, this variant has been classified as Pathogenic. -

Sensorimotor neuropathy Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Abnormality of the musculature Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	28
DANN	Uncertain	0.99
Eigen	Pathogenic	0.83
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		4.7
GERP RS		4.8
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.90		Position offset: -1

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

Other links and lift over

dbSNP: rs398123631; hg19: chr21-47410741;