rs398123631
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_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
NM_001848.3 splice_donor, intron
Scores
2
4
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 4.73
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]
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ACMG classification
Classification made for transcript
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 0.017168771 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 [Likely_pathogenic]. Clinvar id is 17174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-45990827-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-45990827-G-A is described in Lovd as [Pathogenic]. Variant chr21-45990827-G-A is described in Lovd as [Likely_pathogenic]. Variant chr21-45990827-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.1056+1G>A | splice_donor_variant, intron_variant | ENST00000361866.8 | NP_001839.2 |
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:13Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:7
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, Amsterdam University Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 30, 2018 | 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 20, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 15, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Bethlem myopathy 1A Pathogenic:4Other:1
| not provided, no classification provided | literature only | GeneReviews | - | Common variant that results in exon 14 skipping - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2007 | - - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Jun 21, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 13, 2023 | 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. - |
| Pathogenic, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 02, 2023 | 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). - |
Sensorimotor neuropathy Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2017 | - - |
Abnormality of the musculature Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Kariminejad - Najmabadi Pathology & Genetics Center | Jul 10, 2021 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at