VCV000201832.14 - ClinVar

NM_002230.4(JUP):c.849G>T (p.Lys283Asn)

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Uncertain significance

4 out of 6 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002230.4(JUP):c.849G>T (p.Lys283Asn)

Variation ID: 201832 Accession: VCV000201832.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.2 17: 41767439 (GRCh38) [ NCBI UCSC ] 17: 39923691 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Jan 7, 2017	Mar 4, 2025	Dec 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_002230.4:c.849G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002221.1:p.Lys283Asn	missense
NM_001352773.2:c.849G>T	NP_001339702.1:p.Lys283Asn	missense
NM_001352774.2:c.849G>T	NP_001339703.1:p.Lys283Asn	missense
NM_001352775.2:c.849G>T	NP_001339704.1:p.Lys283Asn	missense
NM_001352776.2:c.849G>T	NP_001339705.1:p.Lys283Asn	missense
NM_001352777.2:c.849G>T	NP_001339706.1:p.Lys283Asn	missense
NM_021991.4:c.849G>T	NP_068831.1:p.Lys283Asn	missense
NC_000017.11:g.41767439C>A
NC_000017.10:g.39923691C>A
NG_009090.2:g.24274G>T
LRG_401:g.24274G>T
LRG_401t2:c.849G>T

... more HGVS ... less HGVS

Protein change

K283N

Other names

p.K283N:AAG>AAT

Canonical SPDI

NC_000017.11:41767438:C:A

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00001

The Genome Aggregation Database (gnomAD) 0.00001

Links

ClinGen: CA308571 dbSNP: rs794729054 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
JUP		-	-	GRCh38 GRCh37	1391	1410

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Uncertain significance (3)	criteria provided, single submitter	May 21, 2018	RCV000183510.5
Cardiovascular phenotype	Uncertain significance (1)	criteria provided, single submitter	Oct 23, 2023	RCV002444742.2
Arrhythmogenic right ventricular dysplasia 12 Naxos disease	Uncertain significance (2)	criteria provided, multiple submitters, no conflicts	Dec 22, 2024	RCV001852359.7

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	Expand all rows Collapse all rows Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (May 21, 2018) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Not Provided	GeneDx Accession: SCV000235970.12 First in ClinVar: Jul 05, 2015 Last updated: Jan 07, 2017	Comment: show The K283N variant of uncertain significance in the JUP gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 3/111,686 (0.003%) European (non-Finnish) alleles in large population cohorts (Lek et al., 2016). The K283N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (Dec 22, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Arrhythmogenic right ventricular dysplasia 12 Naxos disease Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases.	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV002196376.3 First in ClinVar: Mar 28, 2022 Last updated: Mar 04, 2025	Comment: show This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 283 of the JUP protein (p.Lys283Asn). This variant is present in population databases (rs794729054, gnomAD 0.003%). 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: 201832). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†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. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Oct 23, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV002678518.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: show The p.K283N variant (also known as c.849G>T), located in coding exon 4 of the JUP gene, results from a G to T substitution at nucleotide position 849. The lysine at codon 283 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Uncertain significance (Apr 04, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Naxos disease Arrhythmogenic right ventricular dysplasia 12	Fulgent Genetics, Fulgent Genetics Accession: SCV002779567.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001739534.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Uncertain significance (-) N Not contributing to aggregate classification	no assertion criteria provided	not provided	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001969864.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Comment:

The K283N variant of uncertain significance in the JUP gene has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 3/111,686 (0.003%) European (non-Finnish) alleles in large population cohorts (Lek et al., 2016). The K283N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. Finally, in-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect.Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign.

Comment:

This sequence change replaces lysine, which is basic and polar, with asparagine, which is neutral and polar, at codon 283 of the JUP protein (p.Lys283Asn). This variant is present in population databases (rs794729054, gnomAD 0.003%). 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: 201832). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬¨‚Ä†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.

Comment:

The p.K283N variant (also known as c.849G>T), located in coding exon 4 of the JUP gene, results from a G to T substitution at nucleotide position 849. The lysine at codon 283 is replaced by asparagine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs794729054 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated May 17, 2025

ClinVar Genomic variation as it relates to human health

NM_002230.4(JUP):c.849G>T (p.Lys283Asn)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs794729054 ...