NM_004415.4(DSP):c.5984T>C (p.Leu1995Ser) AND multiple conditions

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Aug 10, 2023
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:: RCV000794685.6

Allele description [Variation Report for NM_004415.4(DSP):c.5984T>C (p.Leu1995Ser)]

NM_004415.4(DSP):c.5984T>C (p.Leu1995Ser)

Gene:

DSP:desmoplakin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

6p24.3

Genomic location:

Preferred name:

NM_004415.4(DSP):c.5984T>C (p.Leu1995Ser)

Other names:

p.L1995S:TTG>TCG

HGVS:

NC_000006.12:g.7583246T>C
NG_008803.1:g.46610T>C
NM_001008844.3:c.4187T>C
NM_001319034.2:c.4655T>C
NM_004415.4:c.5984T>CMANE SELECT
NP_001008844.1:p.Leu1396Ser
NP_001305963.1:p.Leu1552Ser
NP_004406.2:p.Leu1995Ser
LRG_423t1:c.5984T>C
LRG_423:g.46610T>C
NC_000006.11:g.7583479T>C
NM_004415.2:c.5984T>C

Protein change:

L1396S

Links:

dbSNP: rs794728128

NCBI 1000 Genomes Browser:

rs794728128

Molecular consequence:

NM_001008844.3:c.4187T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001319034.2:c.4655T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_004415.4:c.5984T>C - 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
SCV000934109	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Aug 10, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 31737537, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000934109

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Aug 10, 2023)

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

Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in arrhythmogenic disorders.

Marschall C, Moscu-Gregor A, Klein HG.

Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298. doi: 10.21037/cdt.2019.06.06.

PubMed [citation]

PMID:: 31737537
PMCID:: PMC6837920

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, SCV000934109.4

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

Description

This sequence change replaces leucine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 1995 of the DSP protein (p.Leu1995Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with an arrhythmogenic disorder (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 199897). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests 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

Last Updated: Sep 29, 2024

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