VCV000006585.7 - ClinVar

NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp)

Germline

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.

(4)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp)

Variation ID: 6585 Accession: VCV000006585.7

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 2q37.1 2: 232768790 (GRCh38) [ NCBI UCSC ] 2: 233633500 (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	Jun 27, 2015	Apr 15, 2024	Oct 24, 2022

HGVS

Nucleotide	Protein	Molecular consequence
NM_001103146.3:c.532+7354G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_002242.4:c.484C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002233.2:p.Arg162Trp	missense
NM_001103147.2:c.532+7354G>A		intron variant
NM_001103148.2:c.532+7354G>A		intron variant
NM_001172416.1:c.248C>T	NP_001165887.1:p.Pro83Leu	missense
NM_001172417.1:c.244C>T	NP_001165888.1:p.Arg82Trp	missense
NM_015575.4:c.532+7354G>A		intron variant
NC_000002.12:g.232768790G>A
NC_000002.11:g.233633500G>A
NG_011847.1:g.76486G>A
NG_016742.1:g.12776C>T
	O60928:p.Arg162Trp

... more HGVS ... less HGVS

Protein change

R162W, P83L, R82W

Other names

Canonical SPDI

NC_000002.12:232768789:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

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 0.00000

Links

ClinGen: CA118359 UniProtKB: O60928#VAR_043509 OMIM: 603208.0001 dbSNP: rs121918542 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.
GIGYF2		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh37	145	410
KCNJ13		-	-	GRCh38 GRCh37	-	264

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.
Snowflake vitreoretinal degeneration	Likely pathogenic (3)	criteria provided, multiple submitters, no conflicts	May 5, 2022	RCV000006963.5
not provided	Pathogenic (1)	criteria provided, single submitter	Oct 24, 2022	RCV001389454.5

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.	More information 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.
Likely pathogenic (Jan 30, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Snowflake vitreoretinal degeneration Affected status: yes Allele origin: germline	Institute of Medical Molecular Genetics, University of Zurich Accession: SCV001548007.1 First in ClinVar: Mar 28, 2021 Last updated: Mar 28, 2021	Publications: PubMed (1) PubMed: 33546218 Method: WES
Pathogenic (Oct 24, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001590832.4 First in ClinVar: May 10, 2021 Last updated: Feb 14, 2024	Publications: PubMed (3) PubMed: 18179896‚ 23255580‚ 23977131 Comment: Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) … (more) Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ13 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNJ13 function (PMID: 18179896, 23255580, 23977131). ClinVar contains an entry for this variant (Variation ID: 6585). This missense change has been observed in individual(s) with snowflake vitreoretinal degeneration (PMID: 18179896). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918542, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the KCNJ13 protein (p.Arg162Trp). (less)
Likely pathogenic (May 05, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Snowflake vitreoretinal degeneration Affected status: yes Allele origin: germline	Molecular Genetics, Royal Melbourne Hospital Additional submitter: Shariant Australia, Australian Genomics Accession: SCV004812512.1 First in ClinVar: Apr 15, 2024 Last updated: Apr 15, 2024	Publications: PubMed (4) PubMed: 15557460‚ 18179896‚ 23255580‚ 33546218 Comment: This sequence change is predicted to replace arginine with tryptophan at codon 162 of the KCNJ13 protein, p.(Arg162Trp). The arginine residue is evolutionarily conserved in … (more) This sequence change is predicted to replace arginine with tryptophan at codon 162 of the KCNJ13 protein, p.(Arg162Trp). The arginine residue is evolutionarily conserved in vertebrates (100 vertebrates, UCSC), and is located inward rectifier potassium channel transmembrane domain. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a single individual in a large population cohort (rs121918542, 1/247,900 alleles in gnomAD v2.1). The variant is present in at least three individuals with snowflake vitreoretinal degeneration (SVD) or macular dystrophy, and segregates with SVD over four generations (PMID: 18179896, 15557460, 33546218; Royal Melbourne Hospital). Additionally, in vitro functional assays demonstrate that the variant suppresses the potassium channel activity with a dominant-negative effect (PMID: 18179896, 23255580). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3. (less)
Pathogenic (Mar 01, 2013)	no assertion criteria provided Method: literature only	SNOWFLAKE VITREORETINAL DEGENERATION Affected status: not provided Allele origin: germline	OMIM Accession: SCV000027159.2 First in ClinVar: Apr 04, 2013 Last updated: Jun 27, 2015	Publications: PubMed (2) PubMed: 18179896‚ 23255580 Comment on evidence: In the American family of European extraction in which snowflake vitreoretinal degeneration (SVD; 193230) was first described, Hejtmancik et al. (2008) found that affected members … (more) In the American family of European extraction in which snowflake vitreoretinal degeneration (SVD; 193230) was first described, Hejtmancik et al. (2008) found that affected members were heterozygous for a missense mutation in the KCNJ13 gene, an arg162-to-trp substitution (R162W) that arose from a 484C-T transition. Thirteen members of the family diagnosed with SVD ranged from 12 to 85 years of age at the time of diagnosis. No other families with confirmed SVD were available to test further the association between the KCNJ13 mutation and SVD. R162 of KCNJ13 belongs to a cluster of positively charged residues on the surface of the channel's cytoplasmic domain that interacts with phosphatidylinositol 4,5-bisphosphate in the plasma membrane to gate the channel open. Using immunohistochemical analysis, Zhang et al. (2013) found that both wildtype KCNJ13 and KCNJ13 with the R162W mutation were normally targeted to the plasma membrane in Xenopus oocytes and polarized MDCK cells. However, unlike wildtype KCNJ13, KCNJ13 with the R162W mutation did not develop whole cell currents when expressed in Xenopus oocytes. Coinjection experiments revealed a dominant-negative effect of mutant KCNJ13 on currents produced by wildtype KCNJ13. (less)

Comment:

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KCNJ13 protein function. For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNJ13 function (PMID: 18179896, 23255580, 23977131). ClinVar contains an entry for this variant (Variation ID: 6585). This missense change has been observed in individual(s) with snowflake vitreoretinal degeneration (PMID: 18179896). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121918542, gnomAD 0.006%). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 162 of the KCNJ13 protein (p.Arg162Trp).

Comment:

This sequence change is predicted to replace arginine with tryptophan at codon 162 of the KCNJ13 protein, p.(Arg162Trp). The arginine residue is evolutionarily conserved in vertebrates (100 vertebrates, UCSC), and is located inward rectifier potassium channel transmembrane domain. There is a large physicochemical difference between arginine and tryptophan. The variant is present in a single individual in a large population cohort (rs121918542, 1/247,900 alleles in gnomAD v2.1). The variant is present in at least three individuals with snowflake vitreoretinal degeneration (SVD) or macular dystrophy, and segregates with SVD over four generations (PMID: 18179896, 15557460, 33546218; Royal Melbourne Hospital). Additionally, in vitro functional assays demonstrate that the variant suppresses the potassium channel activity with a dominant-negative effect (PMID: 18179896, 23255580). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (6/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.5.1, this variant is classified as LIKELY PATHOGENIC. Following criteria are met: PP1_Strong, PS3_Supporting, PS4_Supporting, PM2_Supporting, PP3.

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Long-Range PCR-Based NGS Applications to Diagnose Mendelian Retinal Diseases.	Maggi J	International journal of molecular sciences	2021	PMID: 33546218
Snowflake vitreoretinal degeneration (SVD) mutation R162W provides new insights into Kir7.1 ion channel structure and function.	Pattnaik BR	PloS one	2013	PMID: 23977131
Characterization of the R162W Kir7.1 mutation associated with snowflake vitreoretinopathy.	Zhang W	American journal of physiology. Cell physiology	2013	PMID: 23255580
Mutations in KCNJ13 cause autosomal-dominant snowflake vitreoretinal degeneration.	Hejtmancik JF	American journal of human genetics	2008	PMID: 18179896
Genetic linkage of snowflake vitreoretinal degeneration to chromosome 2q36.	Jiao X	Investigative ophthalmology & visual science	2004	PMID: 15557460

Text-mined citations for rs121918542 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918542 ...