NM_004415.4(DSP):c.7778T>G (p.Ile2593Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Jun 17, 2021
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001876062.6

Allele description [Variation Report for NM_004415.4(DSP):c.7778T>G (p.Ile2593Ser)]

NM_004415.4(DSP):c.7778T>G (p.Ile2593Ser)

Gene:

DSP:desmoplakin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_004415.4(DSP):c.7778T>G (p.Ile2593Ser)

HGVS:

NC_000006.12:g.7585040T>G
NG_008803.1:g.48404T>G
NM_001008844.3:c.5981T>G
NM_001319034.2:c.6449T>G
NM_004415.4:c.7778T>GMANE SELECT
NP_001008844.1:p.Ile1994Ser
NP_001305963.1:p.Ile2150Ser
NP_004406.2:p.Ile2593Ser
LRG_423t1:c.7778T>G
LRG_423:g.48404T>G
NC_000006.11:g.7585273T>G
NC_000006.11:g.7585273T>G
NM_004415.2:c.7778T>G

Protein change:

I1994S

Links:

dbSNP: rs563272509

NCBI 1000 Genomes Browser:

rs563272509

Molecular consequence:

NM_001008844.3:c.5981T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001319034.2:c.6449T>G - missense variant - [Sequence Ontology: SO:0001583]
NM_004415.4:c.7778T>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Synonyms:: Palmoplantar keratoderma with left ventricular cardiomyopathy and woolly hair; Epidermolytic palmoplantar keratoderma woolly hair and dilated cardiomyopathy; Dilated cardiomyopathy with woolly hair and keratoderma; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011581; MedGen: C1854063; Orphanet: 65282; OMIM: 605676

Name:: Arrhythmogenic right ventricular dysplasia 8 (ARVD8)
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 8; Arrhythmogenic right ventricular cardiomyopathy, type 8; Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy 8
Identifiers:: MONDO: MONDO:0011831; MedGen: C1843896; OMIM: 607450

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002227639	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Jun 17, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29247119, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002227639

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Jun 17, 2021)

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

Citations

PubMed

Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths.

Lin Y, Williams N, Wang D, Coetzee W, Zhou B, Eng LS, Um SY, Bao R, Devinsky O, McDonald TV, Sampson BA, Tang Y.

Circ Cardiovasc Genet. 2017 Dec;10(6). doi:pii: e001839. 10.1161/CIRCGENETICS.117.001839.

PubMed [citation]

PMID:: 29247119

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

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002227639.3

#	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. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 922453). This variant is present in population databases (rs563272509, ExAC 0.001%). This sequence change replaces isoleucine with serine at codon 2593 of the DSP protein (p.Ile2593Ser). The isoleucine residue is moderately conserved and there is a large physicochemical difference between isoleucine and serine.

#	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 29, 2024

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