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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

Genomes: 𝑓 0.00074 ( 0 hom., cov: 35)
Exomes 𝑓: 0.0014 ( 3 hom. )

Consequence

COL6A1
NM_001848.3 missense

Scores

4
12
3

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:3O:1

Conservation

PhyloP100: 7.60
Variant links:
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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL6A1NM_001848.3 linkuse as main transcriptc.350T>C p.Val117Ala missense_variant 3/35 ENST00000361866.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL6A1ENST00000361866.8 linkuse as main transcriptc.350T>C p.Val117Ala missense_variant 3/351 NM_001848.3 P1

Frequencies

GnomAD3 genomes
AF:
0.000736
AC:
112
AN:
152238
Hom.:
0
Cov.:
35
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000262
Gnomad ASJ
AF:
0.000864
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000376
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00138
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000970
AC:
242
AN:
249608
Hom.:
0
AF XY:
0.000959
AC XY:
130
AN XY:
135562
show subpopulations
Gnomad AFR exome
AF:
0.000187
Gnomad AMR exome
AF:
0.000232
Gnomad ASJ exome
AF:
0.000200
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000325
Gnomad NFE exome
AF:
0.00192
Gnomad OTH exome
AF:
0.000985
GnomAD4 exome
AF:
0.00139
AC:
2031
AN:
1460376
Hom.:
3
Cov.:
33
AF XY:
0.00136
AC XY:
991
AN XY:
726488
show subpopulations
Gnomad4 AFR exome
AF:
0.000239
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.000153
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.000557
Gnomad4 NFE exome
AF:
0.00174
Gnomad4 OTH exome
AF:
0.000696
GnomAD4 genome
AF:
0.000736
AC:
112
AN:
152238
Hom.:
0
Cov.:
35
AF XY:
0.000578
AC XY:
43
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.000169
Gnomad4 AMR
AF:
0.000262
Gnomad4 ASJ
AF:
0.000864
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000376
Gnomad4 NFE
AF:
0.00138
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00113
Hom.:
1
Bravo
AF:
0.000790
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00208
AC:
8
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.00174
AC:
15
ExAC
AF:
0.00126
AC:
152
EpiCase
AF:
0.00104
EpiControl
AF:
0.00160

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3Other:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Jan 03, 2017- -
Likely benign, criteria provided, single submitterclinical testingGeneDxSep 21, 2020Identified 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 providedclinical testingDepartment 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017This 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 providedphenotyping onlyGenomeConnect, 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoJan 13, 2016- -
Bethlem myopathy 1A Benign:1
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 24, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Benign
-0.060
T
BayesDel_noAF
Uncertain
0.13
Cadd
Uncertain
24
Dann
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D;T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.29
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.66
T;T
M_CAP
Pathogenic
0.91
D
MetaRNN
Uncertain
0.57
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.7
M;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.1
D;.
REVEL
Pathogenic
0.80
Sift
Uncertain
0.0070
D;.
Sift4G
Uncertain
0.0020
D;D
Polyphen
1.0
D;.
Vest4
0.72
MVP
0.86
MPC
0.27
ClinPred
0.10
T
GERP RS
4.3
Varity_R
0.24
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs138899581; hg19: chr21-47404305; COSMIC: COSV99054677; COSMIC: COSV99054677; API