NM_002230.4(JUP):c.524C>T (p.Ser175Leu) AND multiple conditions

Germline classification:: Uncertain significance (3 submissions)
Last evaluated:: Feb 3, 2025
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:: RCV001984791.7

Allele description [Variation Report for NM_002230.4(JUP):c.524C>T (p.Ser175Leu)]

NM_002230.4(JUP):c.524C>T (p.Ser175Leu)

Gene:

JUP:junction plakoglobin [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

17q21.2

Genomic location:

Preferred name:

NM_002230.4(JUP):c.524C>T (p.Ser175Leu)

HGVS:

NC_000017.11:g.41769152G>A
NG_009090.2:g.22561C>T
NM_001352773.2:c.524C>T
NM_001352774.2:c.524C>T
NM_001352775.2:c.524C>T
NM_001352776.2:c.524C>T
NM_001352777.2:c.524C>T
NM_002230.3:c.524C>T
NM_002230.4:c.524C>TMANE SELECT
NM_021991.4:c.524C>T
NP_001339702.1:p.Ser175Leu
NP_001339703.1:p.Ser175Leu
NP_001339704.1:p.Ser175Leu
NP_001339705.1:p.Ser175Leu
NP_001339706.1:p.Ser175Leu
NP_002221.1:p.Ser175Leu
NP_068831.1:p.Ser175Leu
LRG_401t2:c.524C>T
LRG_401:g.22561C>T
NC_000017.10:g.39925404G>A
NM_002230.2:c.524C>T
NM_002230.4:c.524C>T

Protein change:

S175L

Links:

dbSNP: rs782435477

NCBI 1000 Genomes Browser:

rs782435477

Molecular consequence:

NM_001352773.2:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352774.2:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352775.2:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352776.2:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352777.2:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002230.4:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021991.4:c.524C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Naxos disease (NXD)
Synonyms:: KERATOSIS PALMOPLANTARIS WITH ARRHYTHMOGENIC CARDIOMYOPATHY; MAL DE NAXOS; PALMOPLANTAR KERATODERMA WITH ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY AND WOOLLY HAIR; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0011017; MedGen: C1832600; Orphanet: 34217; OMIM: 601214

Name:: Arrhythmogenic right ventricular dysplasia 12
Synonyms:: ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 12
Identifiers:: MONDO: MONDO:0012684; MedGen: C1969081; OMIM: 611528

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002207502	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Feb 3, 2025)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002790395	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Sep 15, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV006058454	Department of Pathology and Laboratory Medicine, Sinai Health System	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Jul 30, 2021)	germline	research	PubMed (1) [See all records that cite this PMID]

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002207502

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Feb 3, 2025)

germline

clinical testing

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

SCV002790395

Fulgent Genetics, Fulgent Genetics

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Sep 15, 2021)

unknown

clinical testing

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

SCV006058454

Department of Pathology and Laboratory Medicine, Sinai Health System

criteria provided, single submitter

(ACMG Guidelines, 2015)

Uncertain significance
(Jul 30, 2021)

germline

research

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

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, research
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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002207502.4

#	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 serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 175 of the JUP protein (p.Ser175Leu). This variant is present in population databases (rs782435477, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with JUP-related conditions. ClinVar contains an entry for this variant (Variation ID: 1435077). 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 disruptive. 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 Fulgent Genetics, Fulgent Genetics, SCV002790395.1

#	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 Department of Pathology and Laboratory Medicine, Sinai Health System, SCV006058454.1

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

#	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: May 16, 2025

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Relating variation to medicine