NM_024422.6(DSC2):c.595C>T (p.Arg199Cys) AND Arrhythmogenic right ventricular dysplasia 11

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Jul 12, 2023
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:: RCV000693817.13

Allele description [Variation Report for NM_024422.6(DSC2):c.595C>T (p.Arg199Cys)]

NM_024422.6(DSC2):c.595C>T (p.Arg199Cys)

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.595C>T (p.Arg199Cys)

HGVS:

NC_000018.10:g.31089474G>A
NG_008208.2:g.17952C>T
NM_004949.5:c.595C>T
NM_024422.6:c.595C>TMANE SELECT
NP_004940.1:p.Arg199Cys
NP_077740.1:p.Arg199Cys
LRG_400t1:c.595C>T
LRG_400:g.17952C>T
NC_000018.9:g.28669437G>A
NM_004949.3:c.595C>T
NM_024422.3:c.595C>T
NM_024422.4:c.595C>T

Protein change:

R199C

Links:

dbSNP: rs769787593

NCBI 1000 Genomes Browser:

rs769787593

Molecular consequence:

NM_004949.5:c.595C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024422.6:c.595C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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

Recent activity

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LARGE xylosyl- and glucuronyltransferase 2-like isoform X1 [Neodiprion pinetum]
LARGE xylosyl- and glucuronyltransferase 2-like isoform X1 [Neodiprion pinetum]
gi|2192898533|ref|XP_046487897.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000822236	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jul 12, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28798025, 28492532
SCV001282909	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Jan 12, 2018)	germline	clinical testing	Citation Link,
SCV002581179	MGZ Medical Genetics Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Oct 12, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000822236

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jul 12, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001282909

Illumina Laboratory Services, Illumina

criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)

Uncertain significance
(Jan 12, 2018)

germline

clinical testing

Citation Link,

SCV002581179

MGZ Medical Genetics Center

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Oct 12, 2021)

germline

clinical testing

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

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	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

Novel Genetic Triggers and Genotype-Phenotype Correlations in Patients With Left Ventricular Noncompaction.

Miszalski-Jamka K, Jefferies JL, Mazur W, Głowacki J, Hu J, Lazar M, Gibbs RA, Liczko J, Kłyś J, Venner E, Muzny DM, Rycaj J, Białkowski J, Kluczewska E, Kalarus Z, Jhangiani S, Al-Khalidi H, Kukulski T, Lupski JR, Craigen WJ, Bainbridge MN.

Circ Cardiovasc Genet. 2017 Aug;10(4). doi:pii: e001763. 10.1161/CIRCGENETICS.117.001763.

PubMed [citation]

PMID:: 28798025
PMCID:: PMC5665372

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. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV000822236.6

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

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 496660). This missense change has been observed in individual(s) with left ventricular non-compaction (PMID: 28798025). This variant is present in population databases (rs769787593, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 199 of the DSC2 protein (p.Arg199Cys).

#	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 Illumina Laboratory Services, Illumina, SCV001282909.1

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

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

#	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 MGZ Medical Genetics Center, SCV002581179.1

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

#	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		1	not provided	not provided	not provided

Last Updated: Sep 29, 2024

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