NM_001943.5(DSG2):c.1885C>T (p.Pro629Ser) AND Arrhythmogenic right ventricular dysplasia 10

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Dec 12, 2024
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:: RCV000642309.8

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)

Name:: Arrhythmogenic right ventricular dysplasia 10
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 10; Arrhythmogenic right ventricular cardiomyopathy, type 10; Arrhythmogenic right ventricular dysplasia/cardiomyopathy, type 10; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0012434; MedGen: C1857777; OMIM: 610193

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000763978	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 12, 2024)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 31983221, 32826072, 33652588, 28492532
SCV005398678	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 2, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23071725, 29773157, 30847666, 33652588, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000763978

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 12, 2024)

germline

clinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV005398678

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Feb 2, 2022)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	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

Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.

Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, Wilk A, Whiffin N, Govind R, Mazaika E, de Marvao A, Dawes TJW, Felkin LE, Ahmad M, Theotokis PI, Edwards E, Ing AY, Thomson KL, Chan LLH, Sim D, Baksi AJ, Pantazis A, Roberts AM, Watkins H, et al.

Circulation. 2020 Feb 4;141(5):387-398. doi: 10.1161/CIRCULATIONAHA.119.037661. Epub 2020 Jan 27.

PubMed [citation]

PMID:: 31983221
PMCID:: PMC7004454

Clinical utility of genetic testing in patients with dilated cardiomyopathy.

Peña-Peña ML, Ochoa JP, Barriales-Villa R, Cicerchia M, Palomino-Doza J, Salazar-Mendiguchia J, Lamounier A, Trujillo JP, Garcia-Giustiniani D, Fernandez X, Ortiz-Genga M, Monserrat L, Crespo-Leiro MG.

Med Clin (Barc). 2021 May 21;156(10):485-495. doi: 10.1016/j.medcli.2020.05.067. Epub 2020 Aug 19. English, Spanish.

PubMed [citation]

PMID:: 32826072

See all PubMed Citations (8)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000763978.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

Description

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 629 of the DSG2 protein (p.Pro629Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individual(s) with dilated cardiomyopathy (PMID: 31983221, 32826072, 33652588). ClinVar contains an entry for this variant (Variation ID: 199813). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DSG2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of 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

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV005398678.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as a VUS-3B. Following criteria are met: 0103 - Loss of function and gain of function are reported mechanisms of disease in this gene and are associated with arrhythmogenic right ventricular dysplasia 10 (ARVD 10; MIM#610193) and dilated cardiomyopathy 1BB (DCM; MIM#612877) (ClinVar, PMID: 23071725). (I) 0108 - This gene is associated with both recessive and dominant disease. It is commonly associated to dominant inheritance, however recessive inheritance has been reported in severe DCM patients (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Patients with variants causing ARVC have been reported with a penetrance of 58-75% (OMIM). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (7 heterozygotes, 0 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0710 - Two other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. Two alternative changes to a threonine and a glutamine have each been reported as VUS in individuals with dilated cardiomyopathy and hypertrophic cardiomyopathy, respectively (PMID: 30847666). (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has previously been described as a VUS in multiple individuals with cardiomyopathy or arrhythmogenic right ventricular dysplasia (ClinVar, PMID: 33652588). It has also been reported in one alcoholic cardiomyopathy individual without classification (PMID: 29773157). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

Last Updated: Feb 25, 2025

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