VCV000094911.24 - ClinVar

NM_004369.4(COL6A3):c.175C>T (p.Arg59Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(11)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Conflicting classifications of pathogenicity
Pathogenic(7); Likely pathogenic(1); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004369.4(COL6A3):c.175C>T (p.Arg59Ter)

Variation ID: 94911 Accession: VCV000094911.24

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 237395121 (GRCh38) [ NCBI UCSC ] 2: 238303764 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Dec 6, 2016	Sep 29, 2024	Jan 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_004369.4:c.175C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004360.2:p.Arg59Ter	nonsense
NM_057164.5:c.91+1606C>T		intron variant
NM_057165.5:c.91+1606C>T		intron variant
NM_057166.5:c.91+1606C>T		intron variant
NM_057167.4:c.91+1606C>T		intron variant
NC_000002.12:g.237395121G>A
NC_000002.11:g.238303764G>A
NG_008676.1:g.24087C>T
LRG_473:g.24087C>T
LRG_473t1:c.175C>T	LRG_473p1:p.Arg59Ter

... more HGVS ... less HGVS

Protein change

R59*

Other names

Canonical SPDI

NC_000002.12:237395120:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00003

The Genome Aggregation Database (gnomAD), exomes 0.00004

Exome Aggregation Consortium (ExAC) 0.00007

Trans-Omics for Precision Medicine (TOPMed) 0.00010

Links

ClinGen: CA222591 dbSNP: rs398124119 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
COL6A3		-	-	GRCh38 GRCh37	3260	3461

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Nov 16, 2023	RCV000080916.21
Ullrich congenital muscular dystrophy 1A	Pathogenic/Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jan 16, 2024	RCV000280500.8
Bethlem myopathy 1A	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Oct 13, 2023	RCV000319162.12
Dystonia 27	Pathogenic (1)	criteria provided, single submitter	Aug 7, 2018	RCV000714578.3

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Nov 05, 2012)	criteria provided, single submitter (EGL Classification Definitions) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000331105.4 First in ClinVar: Dec 06, 2016 Last updated: Jul 30, 2019	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A3 Number of individuals with the variant: 1 Sex: mixed
Pathogenic (Sep 30, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002019678.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Oct 13, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Bethlem myopathy 1A Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002240853.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 26004199 Comment: This sequence change creates a premature translational stop signal (p.Arg59) in the COL6A3 gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg59) in the COL6A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL6A3 are known to be pathogenic (PMID: 26004199). This variant is present in population databases (rs398124119, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 94911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Aug 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ullrich congenital muscular dystrophy 1 Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000845282.1 First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018	Number of individuals with the variant: 1 Sex: male Geographic origin: Iran
Pathogenic (Aug 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Dystonia 27 Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000845283.1 First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018	Number of individuals with the variant: 1 Sex: male Geographic origin: Iran
Pathogenic (Aug 07, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Bethlem myopathy 1 Affected status: yes Allele origin: unknown	Genomic Research Center, Shahid Beheshti University of Medical Sciences Accession: SCV000845284.1 First in ClinVar: Nov 03, 2018 Last updated: Nov 03, 2018	Number of individuals with the variant: 1 Sex: male Geographic origin: Iran
Likely pathogenic (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Ullrich congenital muscular dystrophy 1A (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Lifecell International Pvt. Ltd Accession: SCV003842266.1 First in ClinVar: Mar 26, 2023 Last updated: Mar 26, 2023	Comment: A Heterozygous Nonsense variant c.175C>T in Exon 3 of the COL6A3 gene that results in the amino acid substitution p.Arg59* was identified. The observed variant … (more) A Heterozygous Nonsense variant c.175C>T in Exon 3 of the COL6A3 gene that results in the amino acid substitution p.Arg59* was identified. The observed variant has a maximum allele frequency of 0.00004/0.00006 in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID: 94911]. Loss-of-function variants in COL6A3 are known to be pathogenic. For these reasons, this variant has been classified as Likely pathogenic. (less) Ethnicity/Population group: Asian Geographic origin: India
Pathogenic (Jan 16, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Ullrich congenital muscular dystrophy 1A Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV004803466.1 First in ClinVar: Mar 30, 2024 Last updated: Mar 30, 2024	Publications: PubMed (1) PubMed: 31345219 Comment: Variant summary: COL6A3 c.175C>T (p.Arg59X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is … (more) Variant summary: COL6A3 c.175C>T (p.Arg59X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.4e-05 in 249020 control chromosomes. c.175C>T has been reported in the literature in an unspecified individual affected with Cardiovascular disease trait (example, Glicksberg_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31345219). ClinVar contains an entry for this variant (Variation ID: 94911). Based on the evidence outlined above, the variant was classified as pathogenic. (less)
Uncertain significance (Nov 16, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000680917.4 First in ClinVar: Feb 13, 2018 Last updated: Sep 29, 2024	Comment: Reported in an individual with unspecified cardiovascular disease (PMID: 31345219); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene … (more) Reported in an individual with unspecified cardiovascular disease (PMID: 31345219); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 32906206, 31345219, 35925398, 34580720) (less)
Likely pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, Amsterdam University Medical Center Study: VKGL Data-share Consensus Accession: SCV001809060.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021
Pathogenic (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001925064.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
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Comment:

This sequence change creates a premature translational stop signal (p.Arg59*) in the COL6A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL6A3 are known to be pathogenic (PMID: 26004199). This variant is present in population databases (rs398124119, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with COL6A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 94911). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.

Comment:

A Heterozygous Nonsense variant c.175C>T in Exon 3 of the COL6A3 gene that results in the amino acid substitution p.Arg59* was identified. The observed variant has a maximum allele frequency of 0.00004/0.00006 in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic [Variant ID: 94911]. Loss-of-function variants in COL6A3 are known to be pathogenic. For these reasons, this variant has been classified as Likely pathogenic.

Comment:

Variant summary: COL6A3 c.175C>T (p.Arg59X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 4.4e-05 in 249020 control chromosomes. c.175C>T has been reported in the literature in an unspecified individual affected with Cardiovascular disease trait (example, Glicksberg_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 31345219). ClinVar contains an entry for this variant (Variation ID: 94911). Based on the evidence outlined above, the variant was classified as pathogenic.

Comment:

Reported in an individual with unspecified cardiovascular disease (PMID: 31345219); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 32906206, 31345219, 35925398, 34580720)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits.	Glicksberg BS	BMC medical genomics	2019	PMID: 31345219
Recessive mutations in the α3 (VI) collagen gene COL6A3 cause early-onset isolated dystonia.	Zech M	American journal of human genetics	2015	PMID: 26004199
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=COL6A3	-	-	-	-

Text-mined citations for rs398124119 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_004369.4(COL6A3):c.175C>T (p.Arg59Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398124119 ...