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NM_024422.6(DSC2):c.547C>T (p.Arg183Trp) AND not specified

Germline classification:
Uncertain significance (2 submissions)
Last evaluated:
Jul 31, 2018
Review status:
2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV000215449.5

Allele description [Variation Report for NM_024422.6(DSC2):c.547C>T (p.Arg183Trp)]

NM_024422.6(DSC2):c.547C>T (p.Arg183Trp)

Gene:
DSC2:desmocollin 2 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
18q12.1
Genomic location:
Preferred name:
NM_024422.6(DSC2):c.547C>T (p.Arg183Trp)
HGVS:
  • NC_000018.10:g.31089522G>A
  • NG_008208.2:g.17904C>T
  • NM_004949.5:c.547C>T
  • NM_024422.6:c.547C>TMANE SELECT
  • NP_004940.1:p.Arg183Trp
  • NP_077740.1:p.Arg183Trp
  • LRG_400:g.17904C>T
  • NC_000018.9:g.28669485G>A
  • NM_024422.3:c.547C>T
  • NM_024422.4:c.547C>T
Protein change:
R183W
Links:
dbSNP: rs368082152
NCBI 1000 Genomes Browser:
rs368082152
Molecular consequence:
  • NM_004949.5:c.547C>T - missense variant - [Sequence Ontology: SO:0001583]
  • NM_024422.6:c.547C>T - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Synonyms:
AllHighlyPenetrant
Identifiers:
MedGen: CN169374

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV000271707Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
criteria provided, single submitter

(LMM Criteria)		Uncertain significance
(Jun 12, 2015) 		germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000919278Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)		Uncertain significance
(Jul 31, 2018) 		germlineclinical testing

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing
not providedgermlinenot provided11not providednot providednot providedclinical testing

Citations

PubMed

A systematic approach to assessing the clinical significance of genetic variants.

Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS.

Clin Genet. 2013 Nov;84(5):453-63. doi: 10.1111/cge.12257.

PubMed [citation]
PMID:
24033266
PMCID:
PMC3995020

Details of each submission

From Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, SCV000271707.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)

Description

The p.Arg183Trp variant in DSC2 has not been previously reported in individuals with cardiomyopathy, but has been identified in 2/66612 European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs 368082152). Computational prediction tools and conservation analysis suggest tha t the variant may not impact the protein, though this information is not predict ive enough to rule out pathogenicity. In summary, the clinical significance of t he p.Arg183Trp variant is uncertain.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlinenot providednot providednot providednot provided1not provided1not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919278.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

Variant summary: DSC2 c.547C>T (p.Arg183Trp) results in a non-conservative amino acid change located in the first cadherin repeat domain (IPR002126) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.3e-05 in 277034 control chromosomes. The observed variant frequency is approximately 1.7-fold above the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Cardiomyopathy phenotype (2.5e-05), suggesting the variant may be benign. To our knowledge, no occurrence of c.547C>T in individuals affected with Cardiomyopathy and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 12, 2024