VCV002674601.1 - ClinVar

NM_004369.4(COL6A3):c.6238G>T (p.Gly2080Cys)

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.

(1)

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.

Likely pathogenic

criteria provided, single submitter

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_004369.4(COL6A3):c.6238G>T (p.Gly2080Cys)

Variation ID: 2674601 Accession: VCV002674601.1

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.3 2: 237360132 (GRCh38) [ NCBI UCSC ] 2: 238268775 (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 25, 2023	Dec 24, 2023	Dec 21, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_004369.4:c.6238G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_004360.2:p.Gly2080Cys	missense
NM_057164.3:c.5737G>T	NP_476505.2:p.Gly1913Cys	missense
NM_057165.3:c.5638G>T	NP_476506.2:p.Gly1880Cys	missense
NM_057166.5:c.4417G>T	NP_476507.3:p.Gly1473Cys	missense
NM_057167.4:c.5620G>T	NP_476508.2:p.Gly1874Cys	missense
NC_000002.12:g.237360132C>A
NC_000002.11:g.238268775C>A
NG_008676.1:g.59076G>T
LRG_473:g.59076G>T
LRG_473t1:c.6238G>T	LRG_473p1:p.Gly2080Cys

... more HGVS ... less HGVS

Protein change

G1473C, G1874C, G1880C, G1913C, G2080C

Other names

NM_057167.4:c.5620G>T

Canonical SPDI

NC_000002.12:237360131:C: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.

Links

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	3254	3455

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.
Ullrich congenital muscular dystrophy 1A	Likely pathogenic (1)	criteria provided, single submitter	Dec 21, 2023	RCV003454380.2

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.
Likely pathogenic (Dec 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: curation	Ullrich congenital muscular dystrophy 1A (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Study: GREGoR Consortium Accession: SCV004190133.1 First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f4b8450c-8721-4eec-994d-c0cbc8c0dd8c Comment: The p.Gly2080Cys variant in COL6A3 was identified by our study in 1 individual with Ullrich congenital muscular dystrophy 1. This variant is assumed de novo, … (more) The p.Gly2080Cys variant in COL6A3 was identified by our study in 1 individual with Ullrich congenital muscular dystrophy 1. This variant is assumed de novo, but maternity and paternity have not been confirmed. The p.Gly2080Cys variant in COL6A3 has been reported in at least 2 individuals with Ullrich congenital muscular dystrophy ( PMID: 24271325, PMID: 29419890, PMID: 25204870, Neurology Apr 2019, 92 (15 Supplement) P5.4-011), and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position (p.Gly2080Asp, p.Gly2080Arg, and p.Gly2080Ser) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation IDs: 194744, 520883, 502583). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Ullrich congenital muscular dystrophy 1. ACMG/AMP Criteria applied: PM5_strong, PP3, PM2_supporting, PS4_supporting (Richards 2015). (less)

Comment:

The p.Gly2080Cys variant in COL6A3 was identified by our study in 1 individual with Ullrich congenital muscular dystrophy 1. This variant is assumed de novo, but maternity and paternity have not been confirmed. The p.Gly2080Cys variant in COL6A3 has been reported in at least 2 individuals with Ullrich congenital muscular dystrophy ( PMID: 24271325, PMID: 29419890, PMID: 25204870, Neurology Apr 2019, 92 (15 Supplement) P5.4-011), and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position (p.Gly2080Asp, p.Gly2080Arg, and p.Gly2080Ser) have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation IDs: 194744, 520883, 502583). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal dominant Ullrich congenital muscular dystrophy 1. ACMG/AMP Criteria applied: PM5_strong, PP3, PM2_supporting, PS4_supporting (Richards 2015).

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/f4b8450c-8721-4eec-994d-c0cbc8c0dd8c	-	-	-	-

Text-mined citations for this variant ...

Record last updated Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_004369.4(COL6A3):c.6238G>T (p.Gly2080Cys)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for this variant ...