NM_024422.6(DSC2):c.1018A>G (p.Thr340Ala) AND Familial isolated arrhythmogenic right ventricular dysplasia

Germline classification:: Uncertain significance (2 submissions)
Last evaluated:: Jan 3, 2024
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:: RCV000148466.4

Allele description [Variation Report for NM_024422.6(DSC2):c.1018A>G (p.Thr340Ala)]

NM_024422.6(DSC2):c.1018A>G (p.Thr340Ala)

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.1018A>G (p.Thr340Ala)

HGVS:

NC_000018.10:g.31082985T>C
NG_008208.2:g.24441A>G
NM_004949.5:c.1018A>G
NM_024422.6:c.1018A>GMANE SELECT
NP_004940.1:p.Thr340Ala
NP_077740.1:p.Thr340Ala
LRG_400t1:c.1018A>G
LRG_400:g.24441A>G
NC_000018.9:g.28662951T>C
NM_004949.3:c.1018A>G
NM_024422.3:c.1018A>G
NM_024422.4:c.1018A>G
Q02487:p.Thr340Ala

Protein change:

T340A

Links:

UniProtKB: Q02487#VAR_065690; dbSNP: rs368299411

NCBI 1000 Genomes Browser:

rs368299411

Molecular consequence:

NM_004949.5:c.1018A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_024422.6:c.1018A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Familial isolated arrhythmogenic right ventricular dysplasia
Identifiers:: MONDO: MONDO:0016342; MedGen: C4274968; OMIM: PS107970

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000190166	CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation	no assertion criteria provided	Likely benign (Jun 1, 2014)	germline	research
SCV004816186	All of Us Research Program, National Institutes of Health	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain Significance (Jan 3, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 19863551, 25163546, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000190166

CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation

no assertion criteria provided

Likely benign
(Jun 1, 2014)

germline

research

SCV004816186

All of Us Research Program, National Institutes of Health

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain Significance
(Jan 3, 2024)

germline

clinical testing

PubMed (3)
[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	unknown	8	not provided	not provided	108544	not provided	clinical testing, research

Citations

PubMed

Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia.

Barahona-Dussault C, Benito B, Campuzano O, Iglesias A, Leung TL, Robb L, Talajic M, Brugada R.

Clin Genet. 2010 Jan;77(1):37-48. doi: 10.1111/j.1399-0004.2009.01282.x. Epub 2009 Oct 15.

PubMed [citation]

PMID:: 19863551

Atlas of the clinical genetics of human dilated cardiomyopathy.

Haas J, Frese KS, Peil B, Kloos W, Keller A, Nietsch R, Feng Z, Müller S, Kayvanpour E, Vogel B, Sedaghat-Hamedani F, Lim WK, Zhao X, Fradkin D, Köhler D, Fischer S, Franke J, Marquart S, Barb I, Li DT, Amr A, Ehlermann P, et al.

Eur Heart J. 2015 May 7;36(18):1123-35a. doi: 10.1093/eurheartj/ehu301. Epub 2014 Aug 27.

PubMed [citation]

PMID:: 25163546

See all PubMed Citations (3)

Details of each submission

From CSER _CC_NCGL, University of Washington - ESP 6500 variant annotation, SCV000190166.1

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

#	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 All of Us Research Program, National Institutes of Health, SCV004816186.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	8	not provided	not provided	clinical testing	PubMed (3)

Description

This missense variant replaces threonine with alanine at codon 340 of the DSC2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual suspected of having arrhythmogenic right ventricular cardiomyopathy, who also carried a pathogenic truncation variant in the PKP2 gene (PMID: 19863551), and in another individual affected with dilated cardiomyopathy (PMID: 25163546). This variant has been identified in 9/282402 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is 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	108544	not provided	not provided		8	not provided	not provided	not provided

Last Updated: May 7, 2024

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