NM_002230.4(JUP):c.56C>T (p.Thr19Ile) AND not provided

Germline classification:: Uncertain significance (6 submissions)
Last evaluated:: Dec 6, 2022
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:: RCV000656851.12

Allele description [Variation Report for NM_002230.4(JUP):c.56C>T (p.Thr19Ile)]

NM_002230.4(JUP):c.56C>T (p.Thr19Ile)

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.56C>T (p.Thr19Ile)

HGVS:

NC_000017.11:g.41771799G>A
NG_009090.2:g.19914C>T
NM_001352773.2:c.56C>T
NM_001352774.2:c.56C>T
NM_001352775.2:c.56C>T
NM_001352776.2:c.56C>T
NM_001352777.2:c.56C>T
NM_002230.4:c.56C>TMANE SELECT
NM_021991.4:c.56C>T
NP_001339702.1:p.Thr19Ile
NP_001339703.1:p.Thr19Ile
NP_001339704.1:p.Thr19Ile
NP_001339705.1:p.Thr19Ile
NP_001339706.1:p.Thr19Ile
NP_002221.1:p.Thr19Ile
NP_068831.1:p.Thr19Ile
LRG_401t1:c.56C>T
LRG_401t2:c.56C>T
LRG_401:g.19914C>T
NC_000017.10:g.39928051G>A
NM_002230.2:c.56C>T
NM_021991.2:c.56C>T
P14923:p.Thr19Ile

Protein change:

T19I

Links:

UniProtKB: P14923#VAR_065698; dbSNP: rs570878629

NCBI 1000 Genomes Browser:

rs570878629

Molecular consequence:

NM_001352773.2:c.56C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352774.2:c.56C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352775.2:c.56C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352776.2:c.56C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001352777.2:c.56C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_002230.4:c.56C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_021991.4:c.56C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000565085	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Dec 6, 2022)	germline	clinical testing	Citation Link,
SCV001919045	Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001952699	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV001963525	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus	no assertion criteria provided	Uncertain significance	germline	clinical testing
SCV003799543	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2021)	Uncertain significance (Mar 8, 2022)	germline	clinical testing	Citation Link,
SCV005192859	Breakthrough Genomics, Breakthrough Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance	germline	not provided	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	yes	not provided	not provided	not provided	not provided	not provided	clinical testing, not provided
not provided	germline	unknown	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

Details of each submission

From GeneDx, SCV000565085.7

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

Description

Reported in association with dilated cardiomyopathy (DCM) (Garcia-Pavia et al., 2001; Sanchez et al., 2016), and arrhythmogenic right ventricular cardiomyopathy (ARVC) (den Haan et al., 2009; Tan et al., 2010; Bhonsale et al., 2013; Sabater-Molina et al., 2013; te Riele et al., 2015); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27930701, 21859740, 20031617, 20857253, 23671136, 26187847, 27037756, 28471438, 31402444, 34026867, 35581137)

#	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 Clinical Genetics, Academic Medical Center - VKGL Data-share Consensus, SCV001919045.1

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

#	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 Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001952699.1

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

#	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 Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen - VKGL Data-share Consensus, SCV001963525.1

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

#	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 ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV003799543.2

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

Description

The JUP c.56C>T; p.Thr19Ile variant (rs570878629) is reported in the literature in several individuals affected with arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy (Bhonsale 2015, den Haan 2009, Garcia-Pavia 2011, Haggerty 2017, Sanchez 2016, Tan 2010). This variant is also reported in ClinVar (Variation ID: 179756), and is found in the general population with an overall allele frequency of 0.012% (33/280798 alleles) in the Genome Aggregation Database. The threonine at codon 19 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.204). However, given the lack of functional data, the significance of this variant is uncertain at this time. References: Bhonsale A et al. Impact of genotype on clinical course in arrhythmogenic right ventricular dysplasia/cardiomyopathy-associated mutation carriers. Eur Heart J. 2015 Apr 7;36(14):847-55. PMID: 25616645. den Haan AD et al. Comprehensive desmosome mutation analysis in north americans with arrhythmogenic right ventricular dysplasia/cardiomyopathy. Circ Cardiovasc Genet. 2009 Oct;2(5):428-35. PMID: 20031617. Garcia-Pavia P et al. Desmosomal protein gene mutations in patients with idiopathic dilated cardiomyopathy undergoing cardiac transplantation: a clinicopathological study. Heart. 2011 Nov;97(21):1744-52. PMID: 21859740. Haggerty CM et al. Electronic health record phenotype in subjects with genetic variants associated with arrhythmogenic right ventricular cardiomyopathy: a study of 30,716 subjects with exome sequencing. Genet Med. 2017 Nov;19(11):1245-1252. PMID: 28471438. Sanchez O et al. Natural and Undetermined Sudden Death: Value of Post-Mortem Genetic Investigation. PLoS One. 2016 Dec 8;11(12):e0167358. PMID: 27930701. Tan BY et al. Shared desmosome gene findings in early and late onset arrhythmogenic right ventricular dysplasia/cardiomyopathy. J Cardiovasc Transl Res. 2010 Dec;3(6):663-73. PMID: 20857253.

#	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 Breakthrough Genomics, Breakthrough Genomics, SCV005192859.1

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

Last Updated: Jan 13, 2025

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