NM_024422.6(DSC2):c.1018A>G (p.Thr340Ala) AND Arrhythmogenic right ventricular dysplasia 11

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Dec 6, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV000990080.4

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]

Condition(s)

Name:: Arrhythmogenic right ventricular dysplasia 11
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 11; Arrhythmogenic right ventricular cardiomyopathy, type 11; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy11
Identifiers:: MONDO: MONDO:0012506; MedGen: C1864850; OMIM: 610476

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001140867	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Benign (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV003255214	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Dec 6, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 19863551, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001140867

Mendelics

criteria provided, single submitter

(Mendelics Assertion Criteria 2017)

Benign
(May 28, 2019)

unknown

clinical testing

Citation Link,

SCV003255214

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Dec 6, 2023)

germline

clinical testing

PubMed (2)
[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	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240-242.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

Details of each submission

From Mendelics, SCV001140867.1

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

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

From Invitae, SCV003255214.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 340 of the DSC2 protein (p.Thr340Ala). This variant is present in population databases (rs368299411, gnomAD 0.006%). This missense change has been observed in individual(s) with arrhythmogenic right ventricular cardiomyopathy/dysplasia (PMID: 19863551). ClinVar contains an entry for this variant (Variation ID: 161222). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DSC2 protein function with a negative predictive value of 80%. 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

Last Updated: May 7, 2024

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