NM_024422.6(DSC2):c.14G>T (p.Arg5Leu) AND Arrhythmogenic right ventricular dysplasia 11

Germline classification:: Uncertain significance (4 submissions)
Last evaluated:: Mar 19, 2022
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:: RCV001126682.9

Allele description [Variation Report for NM_024422.6(DSC2):c.14G>T (p.Arg5Leu)]

NM_024422.6(DSC2):c.14G>T (p.Arg5Leu)

Genes:

DSCAS:DSC1/DSC2 antisense RNA [Gene - HGNC]
DSC2:desmocollin 2 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

18q12.1

Genomic location:

Preferred name:

NM_024422.6(DSC2):c.14G>T (p.Arg5Leu)

Other names:

p.Arg5Leu

HGVS:

NC_000018.10:g.31101958C>A
NG_008208.2:g.5468G>T
NM_004949.5:c.14G>T
NM_024422.6:c.14G>TMANE SELECT
NP_004940.1:p.Arg5Leu
NP_077740.1:p.Arg5Leu
LRG_400:g.5468G>T
NC_000018.9:g.28681921C>A
NC_000018.9:g.28681921C>A
NM_024422.3:c.14G>T
NM_024422.4:c.14G>T

Protein change:

R5L

Links:

dbSNP: rs899009158

NCBI 1000 Genomes Browser:

rs899009158

Molecular consequence:

NM_004949.5:c.14G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024422.6:c.14G>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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polynucleotide adenylyltransferase region [Nannochloropsis gaditana]
polynucleotide adenylyltransferase region [Nannochloropsis gaditana]
gi|585112281|gb|EWM29703.1||gnl|WGS |Naga_100124g16.8324

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001285909	Illumina Laboratory Services, Illumina	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Uncertain significance (Apr 28, 2017)	germline	clinical testing	Citation Link,
SCV002815775	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Feb 17, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003456864	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 19, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005045530	Clinical Genomics Laboratory, Stanford Medicine	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 21, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Illumina Laboratory Services, Illumina, SCV001285909.1

#	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 as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown 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 Fulgent Genetics, Fulgent Genetics, SCV002815775.1

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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV003456864.1

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

Description

This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 5 of the DSC2 protein (p.Arg5Leu). 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 variant has not been reported in the literature in individuals affected with DSC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 891405). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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 Clinical Genomics Laboratory, Stanford Medicine, SCV005045530.1

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

Description

The p.Arg5Leu variant in the DSC2gene has not been previously reported in association with disease. This variant has been identified in 1/21,118 South Asian chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Computational tools predict that this variant does not impact protein function; however, the accuracy of in silicoalgorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg5Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2; BP4]

#	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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