chr17-41755775-G-A

Variant names:

• chr17-41755775-G-A
• rs151178348
• NM_002230.4:c.2207C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_002230.4(JUP):​c.2207C>T​(p.Pro736Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,609,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P736P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: JUP NM_002230.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:2
• Conservation: PhyloP100: 2.70
• Publications: 2 publications found

Genes affected

JUP (HGNC:6207): (junction plakoglobin) This gene encodes a major cytoplasmic protein which is the only known constituent common to submembranous plaques of both desmosomes and intermediate junctions. This protein forms distinct complexes with cadherins and desmosomal cadherins and is a member of the catenin family since it contains a distinct repeating amino acid motif called the armadillo repeat. Mutation in this gene has been associated with Naxos disease. Alternative splicing occurs in this gene; however, not all transcripts have been fully described. [provided by RefSeq, Jul 2008]

JUP Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 12

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• inherited epidermolysis bullosa

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• Naxos disease

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.106607765).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00021 (32/152280) while in subpopulation NFE AF = 0.000397 (27/68014). AF 95% confidence interval is 0.00028. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
JUP	NM_002230.4	c.2207C>T	p.Pro736Leu	missense_variant	Exon 14 of 14	ENST00000393931.8	NP_002221.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
JUP	ENST00000393931.8	c.2207C>T	p.Pro736Leu	missense_variant	Exon 14 of 14	1	NM_002230.4	ENSP00000377508.3
JUP	ENST00000310706.9	c.2207C>T	p.Pro736Leu	missense_variant	Exon 14 of 15	1		ENSP00000311113.5
JUP	ENST00000393930.5	c.2207C>T	p.Pro736Leu	missense_variant	Exon 14 of 15	5		ENSP00000377507.1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152162 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000263 AC: 65 AN: 247486 AF XY: 0.000276

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000175

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.000145

Gnomad NFE exome AF: 0.000455

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000253 AC: 368 AN: 1456816 Hom.: 0 Cov.: 31 AF XY: 0.000272 AC XY: 197 AN XY: 724242

African (AFR) AF: 0.0000897 AC: 3 AN: 33430

American (AMR) AF: 0.000270 AC: 12 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25926

East Asian (EAS) AF: 0.0000505 AC: 2 AN: 39612

South Asian (SAS) AF: 0.0000818 AC: 7 AN: 85592

European-Finnish (FIN) AF: 0.0000760 AC: 4 AN: 52628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.000291 AC: 323 AN: 1109256

Other (OTH) AF: 0.000282 AC: 17 AN: 60222

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152280 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74454

African (AFR) AF: 0.0000241 AC: 1 AN: 41568

American (AMR) AF: 0.000131 AC: 2 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000406 Hom.: 0

Bravo AF: 0.000272

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000768

EpiControl AF: 0.000834

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Sep 09, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in a patient with Brugada syndrome and a patient with sudden unexplained death (SUD) in published literature (PMID: 26220970, 29334134, 29350269); Identified in patient with epidermolysis bullosa who also harbored several other variants including two COL7A1 variants (PMID: 29334134); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26220970, 29350269, 29334134)

Mar 15, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 17, 2020

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro736Leu variant (rs151178348) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with a frequency of 0.05 percent in the European Non-Finnish population (identified on 58 out of 125,094 chromosomes) and has been reported to the ClinVar database (Variation ID: 45847). The proline at position 736 is weakly conserved and computational analyses of the effects of the p.Pro736Leu variant on protein structure and function provide conflicting results (SIFT: tolerated, MutationTaster: disease causing, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Pro736Leu variant with certainty.

Jun 12, 2020

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Naxos disease Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Sep 16, 2021

Clinical Genomics Laboratory, Stanford Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro736Leu variant in the JUP gene has been previously reported in an individual with Brugada syndrome (Di Resta et al., 2015). This variant was also identified in an epidermolysis bullosa cohort in an individual with several other reported variants (Lucky et al., 2018). This variant has been identified in 56/127,498 European non-Finnish chromosomes (72/278,860 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been observed in the general population, it has not been observed at a frequency high enough to rule out pathogenicity. The proline at position 736 is not evolutionarily conserved. Computational tools predict that the p.Pro736Leu variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro736Leu variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP4]

Naxos disease;C1969081:Arrhythmogenic right ventricular dysplasia 12 Uncertain:2

Aug 10, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 736 of the JUP protein (p.Pro736Leu). This variant is present in population databases (rs151178348, gnomAD 0.05%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 26220970). ClinVar contains an entry for this variant (Variation ID: 45847). 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. 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.

not specified Uncertain:1 Benign:1

Dec 18, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: JUP c.2207C>T (p.Pro736Leu) results in a non-conservative amino acid change in the encoded protein sequence. Two of four in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 247486 control chromosomes. The observed variant frequency is approximately 42 fold of the estimated maximal expected allele frequency for a pathogenic variant in JUP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (6.3e-06), strongly suggesting that the variant is benign. c.2207C>T has been reported in the literature in individuals affected with Brugada Syndrome and sudden unexplained death (DiResta_2015, Neubauer_2018). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: eight submitters classified the variant as VUS while one classified as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.

Apr 01, 2015

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Pro736Leu variant in JUP has been identified by our laboratory in 4 indivi duals (1 child with HCM, 1 adult and 1 child with DCM, and 1 child with RCM), 2 of whom carried clinically significant variants in other genes. This variant has also been identified in 0.04% (28/64990) of European chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs151178348). Proline (Pro) at position 736 is not conserved in evolution and 1 mammal (Tenre c) carries a leucine (Leu) at this position, raising the possibility that this c hange may be tolerated. In summary, the clinical significance of the p.Pro736Leu variant is uncertain.

Arrhythmogenic right ventricular dysplasia 12 Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Left ventricular noncompaction cardiomyopathy Uncertain:1

Jul 23, 2014

Blueprint Genetics

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

Cardiovascular phenotype Benign:1

May 03, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	23
DANN	Benign	0.76
DEOGEN2	Benign	0.25	T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0086
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.0	.;.;T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.76	N;N;N
PhyloP100		2.7
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.21	N;N;N
REVEL	Benign	0.080
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.60	T;T;T
Vest4		0.21
ClinPred		0.027	T
GERP RS		5.0
Varity_R		0.068
gMVP		0.69
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs151178348; hg19: chr17-39912027;