NM_001943.5(DSG2):c.1885C>T (p.Pro629Ser) AND not specified

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Nov 5, 2018
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV000223710.3

Allele description [Variation Report for NM_001943.5(DSG2):c.1885C>T (p.Pro629Ser)]

NM_001943.5(DSG2):c.1885C>T (p.Pro629Ser)

Gene:

DSG2:desmoglein 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_001943.5(DSG2):c.1885C>T (p.Pro629Ser)

Other names:

p.P629S:CCA>TCA

HGVS:

NC_000018.10:g.31541198C>T
NG_007072.3:g.47957C>T
NM_001943.5:c.1885C>TMANE SELECT
NP_001934.2:p.Pro629Ser
LRG_397t1:c.1885C>T
LRG_397:g.47957C>T
NC_000018.9:g.29121161C>T
NM_001943.3:c.1885C>T
NM_001943.4:c.1885C>T

Protein change:

P629S

Links:

dbSNP: rs200804638

NCBI 1000 Genomes Browser:

rs200804638

Molecular consequence:

NM_001943.5:c.1885C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000280083	Stanford Center for Inherited Cardiovascular Disease, Stanford University	no assertion criteria provided	Uncertain significance (Mar 20, 2014)	germline	clinical testing
SCV000919282	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Nov 5, 2018)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000280083

Stanford Center for Inherited Cardiovascular Disease, Stanford University

no assertion criteria provided

Uncertain significance
(Mar 20, 2014)

germline

clinical testing

SCV000919282

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Nov 5, 2018)

germline

clinical testing

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

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Genetic Etiology for Alcohol-Induced Cardiac Toxicity.

Ware JS, Amor-Salamanca A, Tayal U, Govind R, Serrano I, Salazar-Mendiguchía J, García-Pinilla JM, Pascual-Figal DA, Nuñez J, Guzzo-Merello G, Gonzalez-Vioque E, Bardaji A, Manito N, López-Garrido MA, Padron-Barthe L, Edwards E, Whiffin N, Walsh R, Buchan RJ, Midwinter W, Wilk A, Prasad S, et al.

J Am Coll Cardiol. 2018 May 22;71(20):2293-2302. doi: 10.1016/j.jacc.2018.03.462.

PubMed [citation]

PMID:: 29773157
PMCID:: PMC5957753

Details of each submission

From Stanford Center for Inherited Cardiovascular Disease, Stanford University, SCV000280083.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. Based on the data reviewed below, we would categorize this as a variant of unknown significance (VUS). This variant has not been reported in the scientific literature as a disease-causing mutation nor as a benign polymorphism to our knowledge. This is a non-conservative amino acid substitution in which a non-polar Proline is replaced by a neutral, polar Serine at a residue that is conserved across species. In silico analysis with PolyPhen-2 predicts the variant to be “probably damaging” with a score of 1.0. Only one missense variant at a nearby residue has been reported in HGMD in association with ARVC, which may or may not support the functional importance of this region of the protein: Gly638Arg (HGMD professional version as of January 17, 2014). The variant has not been seen in ~6200 individuals from population datasets. It is not listed in the NHLBI Exome Sequencing Project (ESP) dataset, which currently includes variant calls on ~4200 Caucasian and ~2000 African American individuals. The phenotype of the ESP individuals is not publicly available, however the cohorts that were merged to create this dataset were all either general population samples or samples recruited for common cardiovascular disease such as hypertension. There is also no variant at codon 629 listed in 1000 genomes (as of March 20, 2014). The Pro629Ser variant is listed in dbSNP.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000919282.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

Variant summary: DSG2 c.1885C>T (p.Pro629Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 246854 control chromosomes (gnomAD and publication). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.1885C>T, has been reported in the literature in one individual affected with Alcoholic Cardiomyopathy (Ware_2018), together with the pathogenic TTN .43144_43147delCTGG (p.Leu14382ValfsTer2). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Feb 25, 2025

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