NM_024422.6(DSC2):c.1123C>T (p.Arg375Ter) AND Arrhythmogenic right ventricular dysplasia 11

This record was updated by the submitter. Please see the current version.

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 21, 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:: RCV001855862.6

Allele description

NM_024422.6(DSC2):c.1123C>T (p.Arg375Ter)

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.1123C>T (p.Arg375Ter)

HGVS:

NC_000018.10:g.31082378G>A
NG_008208.2:g.25048C>T
NM_004949.5:c.1123C>T
NM_024422.6:c.1123C>TMANE SELECT
NP_004940.1:p.Arg375Ter
NP_077740.1:p.Arg375Ter
LRG_400t1:c.1123C>T
LRG_400:g.25048C>T
NC_000018.9:g.28662344G>A
NM_004949.3:c.1123C>T
NM_024422.3:c.1123C>T
NM_024422.4:c.1123C>T

Protein change:

R375*

Links:

dbSNP: rs794728075

NCBI 1000 Genomes Browser:

rs794728075

Molecular consequence:

NM_004949.5:c.1123C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_024422.6:c.1123C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV002129649	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 23, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23911551, 28492532
SCV004040851	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 3, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004239085	Johns Hopkins Genomics, Johns Hopkins University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 21, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 23911551, 30122538, 32686758, 34012068, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002129649

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 23, 2021)

germline

clinical testing

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

SCV004040851

Baylor Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Apr 3, 2023)

unknown

clinical testing

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

SCV004239085

Johns Hopkins Genomics, Johns Hopkins University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Aug 21, 2023)

germline

clinical testing

PubMed (5)
[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	unknown	unknown	not provided	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

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

Mechanistic basis of desmosome-targeted diseases.

Al-Jassar C, Bikker H, Overduin M, Chidgey M.

J Mol Biol. 2013 Nov 1;425(21):4006-22. doi: 10.1016/j.jmb.2013.07.035. Epub 2013 Aug 2. Review.

PubMed [citation]

PMID:: 23911551
PMCID:: PMC3807649

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV002129649.3

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

Description

This variant has not been reported in the literature in individuals affected with DSC2-related conditions. This sequence change creates a premature translational stop signal (p.Arg375*) in the DSC2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in DSC2 are known to be pathogenic (PMID: 23911551). This variant is present in population databases (no rsID available, gnomAD 0.003%). ClinVar contains an entry for this variant (Variation ID: 617896). For these reasons, this variant has been classified as Pathogenic.

#	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 Baylor Genetics, SCV004040851.1

#	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 Johns Hopkins Genomics, Johns Hopkins University, SCV004239085.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This DSC2 variant (rs794728075) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 2/251006 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar and in the literature as a secondary finding following genomic-based testing. This nonsense variant results in a premature termination codon (PTC) in exon 9 of 16, likely leading to nonsense-mediated decay and lack of protein production. Bioinformatic analysis predicts that this missense variant would not affect normal exon 9 splicing, although this has not been confirmed experimentally to our knowledge. We consider c.1123C>T (p.Arg375Ter) to be pathogenic for arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C).

#	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: Sep 16, 2024

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