VCV000128241.20 - ClinVar

NM_018474.6(KIZ):c.226C>T (p.Arg76Ter)

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.

(11)

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

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_018474.6(KIZ):c.226C>T (p.Arg76Ter)

Variation ID: 128241 Accession: VCV000128241.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 20p11.23 20: 21136463 (GRCh38) [ NCBI UCSC ] 20: 21117104 (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	May 17, 2014	Feb 14, 2024	Jan 29, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_018474.6(KIZ):c.226C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NM_018474.6:c.226C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_060944.3:p.Arg76Ter	nonsense
NM_001163022.3:c.6+4304C>T		intron variant
NM_001163023.3:c.6+4304C>T		intron variant
NM_001276389.2:c.169-9102C>T		intron variant
NM_001352434.2:c.226C>T	NP_001339363.1:p.Arg76Ter	nonsense
NM_001352435.2:c.6+4304C>T		intron variant
NM_001352436.2:c.-161C>T		5 prime UTR
NC_000020.11:g.21136463C>T
NC_000020.10:g.21117104C>T
NG_033122.2:g.15484C>T

... more HGVS ... less HGVS

Protein change

R76*

Other names

KIZ, ARG76TER (rs202210819)

Canonical SPDI

NC_000020.11:21136462:C:T

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) 0.00032

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00042

The Genome Aggregation Database (gnomAD), exomes 0.00049

Trans-Omics for Precision Medicine (TOPMed) 0.00049

Exome Aggregation Consortium (ExAC) 0.00095

Links

ClinGen: CA151548 OMIM: 615757.0001 dbSNP: rs202210819 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.
KIZ		-	-	GRCh38 GRCh37	303	465
LOC130065509	-	-	-	GRCh38	-	27

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.
Retinitis pigmentosa 69	Pathogenic (6)	criteria provided, multiple submitters, no conflicts	Dec 15, 2022	RCV000116208.13
Retinal dystrophy	Pathogenic (1)	criteria provided, single submitter	Jul 27, 2019	RCV001073648.2
Retinitis pigmentosa	Pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001003070.1
KIZ-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 14, 2023	RCV003390800.4
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 29, 2024	RCV000760516.9

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.
Pathogenic (Jan 29, 2024)	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: SCV001208150.5 First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024	Publications: PubMed (5) PubMed: 24680887‚ 29057815‚ 28837078‚ 31556760‚ 32052671 Comment: This sequence change creates a premature translational stop signal (p.Arg76) in the KIZ gene. It is expected to result in an absent or disrupted protein … (more) This sequence change creates a premature translational stop signal (p.Arg76) in the KIZ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIZ are known to be pathogenic (PMID: 24680887, 29057815). This variant is present in population databases (rs202210819, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 24680887, 28837078, 29057815, 31556760, 32052671; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128241). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 27, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239199.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Dec 15, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 69 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003818832.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Apr 08, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Retinitis pigmentosa 69 Affected status: yes Allele origin: germline	Ocular Genomics Institute, Massachusetts Eye and Ear Accession: SCV001573450.1 First in ClinVar: May 10, 2021 Last updated: May 10, 2021	Publications: PubMed (5) PubMed: 29057815‚ 28837078‚ 24680887‚ 31556760‚ 32052671 Comment: The PLK1S1 c.226C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we … (more) The PLK1S1 c.226C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM3, PP4. Based on this evidence we have classified this variant as Pathogenic. (less)
Pathogenic (Dec 15, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000890407.3 First in ClinVar: Mar 19, 2019 Last updated: Dec 31, 2022	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28837078, 24680887, 29057815, 30081015, 31556760, 31456290, 34662339, 36317312, 32052671) (less)
Pathogenic (Oct 19, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 69 Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002813808.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Pathogenic (Aug 14, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	KIZ-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004120586.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The KIZ c.226C>T variant is predicted to result in premature protein termination (p.Arg76). This variant has been reported in the homozygous and compound heterozygous states … (more) The KIZ c.226C>T variant is predicted to result in premature protein termination (p.Arg76). This variant has been reported in the homozygous and compound heterozygous states in individuals with rod-cone dystrophy (El Shamieh et al. 2014. PubMed ID: 24680887; El Shamieh et al. 2017. PubMed ID: 29057815; Gustafson et al. 2017. PubMed ID: 28837078; Table S2 in Sharon et al. 2019. PubMed ID: 31456290). This variant is reported in 0.63% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-21117104-C-T). Nonsense variants in KIZ are expected to be pathogenic. Given the evidence, we interpret c.226C>T (p.Arg76*) as pathogenic. (less)
Pathogenic (Jun 23, 2019)	no assertion criteria provided Method: research	Retinitis pigmentosa Affected status: yes Allele origin: inherited	Sharon lab, Hadassah-Hebrew University Medical Center Accession: SCV001161127.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020
Pathogenic (Apr 03, 2014)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 69 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000150117.1 First in ClinVar: May 17, 2014 Last updated: May 17, 2014	Publications: PubMed (1) PubMed: 24680887 Comment on evidence: In 2 unrelated men with retinitis pigmentosa (RP69; 615780), 1 of North African Sephardic Jewish ancestry and the other of Spanish ancestry, El Shamieh et … (more) In 2 unrelated men with retinitis pigmentosa (RP69; 615780), 1 of North African Sephardic Jewish ancestry and the other of Spanish ancestry, El Shamieh et al. (2014) identified homozygosity for a c.226C-T transition in exon 3 of the KIZ gene, resulting in an arg76-to-ter (R76X) substitution. This rare variant (rs202210819), which segregated with disease in the consanguineous North African family, was found in heterozygosity in 5 European Americans among 5,920 individuals in the NHLBI Exome Variant Server (MAF = 0.0004 in European Americans). Haplotype analysis in the 2 affected men revealed that they shared a common haplotype of 5 polymorphic microsatellites flanking KIZ, suggesting that R76X represents a founder mutation causing autosomal recessive RP in the southern European population. (less)
Pathogenic (Jan 06, 2020)	no assertion criteria provided Method: curation	Retinitis pigmentosa 69 Affected status: unknown Allele origin: germline	Reproductive Health Research and Development, BGI Genomics Accession: SCV001142495.1 First in ClinVar: Jan 12, 2020 Last updated: Jan 12, 2020	Comment: NM_018474.5:c.226C>T in the KIZ gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Arg76* (NM_018474.5:c.226C>T) variant in the … (more) NM_018474.5:c.226C>T in the KIZ gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Arg76* (NM_018474.5:c.226C>T) variant in the KIZ gene has been reported in retinitis pigmentosa patients with a homozygous mutation (PMID: 24680887; 2905781). This variant is presented in the biological transcript and located at the 3/13 exon, therefore, it is predicted to lead nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4. (less)
Pathogenic (Jun 05, 2023)	no assertion criteria provided Method: curation	Retinitis pigmentosa 69 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001445951.2 First in ClinVar: Nov 21, 2020 Last updated: Jun 10, 2023	Publications: PubMed (5) PubMed: 31556760‚ 24680887‚ 29057815‚ 28837078‚ 32052671 Comment: The homozygous p.Arg76Ter variant in KIZ was identified by our study in 2 siblings with retinitis pigmentosa. The variant has been reported in 9 individuals … (more) The homozygous p.Arg76Ter variant in KIZ was identified by our study in 2 siblings with retinitis pigmentosa. The variant has been reported in 9 individuals with retinitis pigmentosa (PMID: 28837078, 24680887, 29057815, 32052671, 31556760), segregated with disease in 2 affected relatives from 2 families (PMID: 28837078), and has been identified in 0.63% (61/9658) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs202210819). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 128241) as pathogenic by GeneDx, OMIM, Sharon lab, Hadassah-Hebrew University Medical Center, and Reproductive Health Research and Development, BGI Genomics. Of the 9 affected individuals, all were homozygotes, which increases the likelihood that the p.Arg76Ter variant is pathogenic (PMID: 28837078, 24680887, 29057815, 32052671, 31556760). This nonsense variant leads to a premature termination codon at position 76, which is predicted to lead to a truncated or absent protein. Loss of function of the KIZ gene is an established disease mechanism in autosomal recessive retinitis pigmentosa. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa. ACMG/AMP Criteria applied: PVS1, PM3, PP1 (Richards 2015). (less)
click to load more click to collapse

Comment:

This sequence change creates a premature translational stop signal (p.Arg76*) in the KIZ gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIZ are known to be pathogenic (PMID: 24680887, 29057815). This variant is present in population databases (rs202210819, gnomAD 0.7%), and has an allele count higher than expected for a pathogenic variant. This premature translational stop signal has been observed in individual(s) with clinical features of retinitis pigmentosa (PMID: 24680887, 28837078, 29057815, 31556760, 32052671; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 128241). For these reasons, this variant has been classified as Pathogenic.

Comment:

The PLK1S1 c.226C>T variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PVS1, PM3, PP4. Based on this evidence we have classified this variant as Pathogenic.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 28837078, 24680887, 29057815, 30081015, 31556760, 31456290, 34662339, 36317312, 32052671)

Comment:

The KIZ c.226C>T variant is predicted to result in premature protein termination (p.Arg76*). This variant has been reported in the homozygous and compound heterozygous states in individuals with rod-cone dystrophy (El Shamieh et al. 2014. PubMed ID: 24680887; El Shamieh et al. 2017. PubMed ID: 29057815; Gustafson et al. 2017. PubMed ID: 28837078; Table S2 in Sharon et al. 2019. PubMed ID: 31456290). This variant is reported in 0.63% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/20-21117104-C-T). Nonsense variants in KIZ are expected to be pathogenic. Given the evidence, we interpret c.226C>T (p.Arg76*) as pathogenic.

Comment:

NM_018474.5:c.226C>T in the KIZ gene has an allele frequency of 0.006 in Ashkenazi Jewish subpopulation in the gnomAD database. The p.Arg76* (NM_018474.5:c.226C>T) variant in the KIZ gene has been reported in retinitis pigmentosa patients with a homozygous mutation (PMID: 24680887; 2905781). This variant is presented in the biological transcript and located at the 3/13 exon, therefore, it is predicted to lead nonsense-mediated mRNA decay. Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PVS1; PM3; PP4.

Comment:

The homozygous p.Arg76Ter variant in KIZ was identified by our study in 2 siblings with retinitis pigmentosa. The variant has been reported in 9 individuals with retinitis pigmentosa (PMID: 28837078, 24680887, 29057815, 32052671, 31556760), segregated with disease in 2 affected relatives from 2 families (PMID: 28837078), and has been identified in 0.63% (61/9658) of Ashkenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs202210819). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 128241) as pathogenic by GeneDx, OMIM, Sharon lab, Hadassah-Hebrew University Medical Center, and Reproductive Health Research and Development, BGI Genomics. Of the 9 affected individuals, all were homozygotes, which increases the likelihood that the p.Arg76Ter variant is pathogenic (PMID: 28837078, 24680887, 29057815, 32052671, 31556760). This nonsense variant leads to a premature termination codon at position 76, which is predicted to lead to a truncated or absent protein. Loss of function of the KIZ gene is an established disease mechanism in autosomal recessive retinitis pigmentosa. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive retinitis pigmentosa. ACMG/AMP Criteria applied: PVS1, PM3, PP1 (Richards 2015).

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
Progressive RPE atrophy and photoreceptor death in KIZ-associated autosomal recessive retinitis pigmentosa.	Lin Y	Ophthalmic genetics	2020	PMID: 32052671
Retinal dystrophy associated with a Kizuna (KIZ) mutation and a predominantly macular phenotype.	Zhao Y	Ophthalmic genetics	2019	PMID: 31556760
Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy.	El Shamieh S	Genes	2017	PMID: 29057815
Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree.	Gustafson K	Genes	2017	PMID: 28837078
Whole-exome sequencing identifies KIZ as a ciliary gene associated with autosomal-recessive rod-cone dystrophy.	El Shamieh S	American journal of human genetics	2014	PMID: 24680887

Text-mined citations for rs202210819 ...

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_018474.6(KIZ):c.226C>T (p.Arg76Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs202210819 ...