rs138899581
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.
The NM_001848.3(COL6A1):c.350T>C(p.Val117Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,612,614 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V117M) has been classified as Likely benign.
Frequency
Consequence
NM_001848.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL6A1 | NM_001848.3 | c.350T>C | p.Val117Ala | missense_variant | 3/35 | ENST00000361866.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL6A1 | ENST00000361866.8 | c.350T>C | p.Val117Ala | missense_variant | 3/35 | 1 | NM_001848.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000736 AC: 112AN: 152238Hom.: 0 Cov.: 35
GnomAD3 exomes AF: 0.000970 AC: 242AN: 249608Hom.: 0 AF XY: 0.000959 AC XY: 130AN XY: 135562
GnomAD4 exome AF: 0.00139 AC: 2031AN: 1460376Hom.: 3 Cov.: 33 AF XY: 0.00136 AC XY: 991AN XY: 726488
GnomAD4 genome ? AF: 0.000736 AC: 112AN: 152238Hom.: 0 Cov.: 35 AF XY: 0.000578 AC XY: 43AN XY: 74386
ClinVar
Submissions by phenotype
not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jan 03, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2020 | Identified in a patient with Ullrich congenital muscular dystrophy, without a second variant, and was inherited from an unaffected parent (Bovolenta et al., 2010); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30564623, 20302629, 23040494) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The COL6A1 p.Val117Ala variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs138899581), LOVD 3.0 and ClinVar (classified as a VUS by EGL Genetic Diagnostics and University of Chicago Genetic Services Laboratory and classified as likely benign by Illumina and Invitae). The variant was identified in control databases in 264 of 280992 chromosomes at a frequency of 0.00094 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 235 of 127820 chromosomes (freq: 0.001839), Other in 6 of 7180 chromosomes (freq: 0.000836), European (Finnish) in 10 of 25020 chromosomes (freq: 0.0004), Latino in 8 of 35396 chromosomes (freq: 0.000226), Ashkenazi Jewish in 2 of 10282 chromosomes (freq: 0.000195) and African in 3 of 24762 chromosomes (freq: 0.000121); it was not observed in the East Asian and South Asian populations. This variant was identified in 2/141 patients with Down Syndrome and atrioventricular septal defects (Ackerman_2012_PMID: 23040494). The variant occurs outside of the splicing consensus sequence and four out of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, and GeneSplicer) do not predict a greater than 10% difference in splicing. The p.Val117 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, and MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Collagen 6-related myopathy Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jan 13, 2016 | - - |
Bethlem myopathy 1A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at