NM_024422.6(DSC2):c.1789G>T (p.Val597Phe) AND not specified

Germline classification:: Likely benign (3 submissions)
Last evaluated:: Apr 9, 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:: RCV000181179.6

Allele description [Variation Report for NM_024422.6(DSC2):c.1789G>T (p.Val597Phe)]

NM_024422.6(DSC2):c.1789G>T (p.Val597Phe)

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.1789G>T (p.Val597Phe)

Other names:

p.V597F:GTT>TTT

HGVS:

NC_000018.10:g.31074782C>A
NG_008208.2:g.32644G>T
NM_004949.5:c.1789G>T
NM_024422.6:c.1789G>TMANE SELECT
NP_004940.1:p.Val597Phe
NP_077740.1:p.Val597Phe
LRG_400:g.32644G>T
NC_000018.9:g.28654748C>A
NM_024422.3:c.1789G>T
NM_024422.4:c.1789G>T

Protein change:

V597F

Links:

dbSNP: rs143040393

NCBI 1000 Genomes Browser:

rs143040393

Molecular consequence:

NM_004949.5:c.1789G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_024422.6:c.1789G>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000233456	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely benign (May 31, 2017)	germline	clinical testing	Citation Link,
SCV001433082	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	criteria provided, single submitter (ACMG Guidelines, 2015)	Likely benign (Oct 19, 2019)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005076876	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely benign (Apr 9, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000233456

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Likely benign
(May 31, 2017)

germline

clinical testing

Citation Link,

SCV001433082

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

criteria provided, single submitter

(ACMG Guidelines, 2015)

Likely benign
(Oct 19, 2019)

germline

clinical testing

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

SCV005076876

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely benign
(Apr 9, 2024)

germline

clinical testing

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

Citation Link

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	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

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

Post-mortem genetic analysis in juvenile cases of sudden cardiac death.

Campuzano O, Sanchez-Molero O, Allegue C, Coll M, Mademont-Soler I, Selga E, Ferrer-Costa C, Mates J, Iglesias A, Sarquella-Brugada G, Cesar S, Brugada J, Castellà J, Medallo J, Brugada R.

Forensic Sci Int. 2014 Dec;245:30-7. doi: 10.1016/j.forsciint.2014.10.004. Epub 2014 Oct 14.

PubMed [citation]

PMID:: 25447171

Details of each submission

From GeneDx, SCV000233456.11

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

Description

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

#	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

From Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute, SCV001433082.1

#	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	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005076876.1

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

Description

Variant summary: DSC2 c.1789G>T (p.Val597Phe) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251108 control chromosomes, predominantly at a frequency of 0.0022 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSC2 causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.00016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1789G>T has been reported in the literature in individuals affected with sudden cardiac death and was evaluated as a benign variant (Campuzano_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25447171). ClinVar contains an entry for this variant (Variation ID: 199784). Based on the evidence outlined above, the variant was classified as likely benign.

#	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: Jul 23, 2024

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