NM_018474.6(KIZ):c.226C>T (p.Arg76Ter) AND Retinitis pigmentosa 69

Germline classification:: Pathogenic (6 submissions)
Last evaluated:: Dec 15, 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:: RCV000116208.13

Allele description [Variation Report for NM_018474.6(KIZ):c.226C>T (p.Arg76Ter)]

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

Genes:

LOC130065509:ATAC-STARR-seq lymphoblastoid active region 17619 [Gene]
KIZ:kizuna centrosomal protein [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

20p11.23

Genomic location:

Preferred name:

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

Other names:

KIZ, ARG76TER (rs202210819)

HGVS:

NC_000020.11:g.21136463C>T
NG_033122.2:g.15484C>T
NM_001163022.3:c.6+4304C>T
NM_001163023.3:c.6+4304C>T
NM_001276389.2:c.169-9102C>T
NM_001352434.2:c.226C>T
NM_001352435.2:c.6+4304C>T
NM_001352436.2:c.-161C>T
NM_018474.6:c.226C>TMANE SELECT
NP_001339363.1:p.Arg76Ter
NP_060944.3:p.Arg76Ter
NC_000020.10:g.21117104C>T
NM_018474.4:c.226C>T
NM_018474.5:c.226C>T
NM_018474.6(KIZ):c.226C>TMANE SELECT
p.Arg76Ter

Protein change:

R76*; ARG76TER

Links:

OMIM: 615757.0001; dbSNP: rs202210819

NCBI 1000 Genomes Browser:

rs202210819

Molecular consequence:

NM_001352436.2:c.-161C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001163022.3:c.6+4304C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001163023.3:c.6+4304C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001276389.2:c.169-9102C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001352435.2:c.6+4304C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_001352434.2:c.226C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_018474.6:c.226C>T - nonsense - [Sequence Ontology: SO:0001587]

Condition(s)

Name:: Retinitis pigmentosa 69 (RP69)
Identifiers:: MONDO: MONDO:0014345; MedGen: C4014312; Orphanet: 791; OMIM: 615780

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000150117	OMIM	no assertion criteria provided	Pathogenic (Apr 3, 2014)	germline	literature only	PubMed (1) [See all records that cite this PMID]
SCV001142495	Reproductive Health Research and Development, BGI Genomics	no assertion criteria provided	Pathogenic (Jan 6, 2020)	germline	curation
SCV001445951	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	no assertion criteria provided	Pathogenic (Jun 5, 2023)	germline	curation	PubMed (5) [See all records that cite these PMIDs] 31556760, 24680887, 29057815, 28837078, 32052671
SCV001573450	Ocular Genomics Institute, Massachusetts Eye and Ear	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 8, 2021)	germline	research	PubMed (6) [See all records that cite these PMIDs] 29057815, 28837078, 24680887, 31556760, 32052671, 25741868
SCV002813808	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 19, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003818832	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 15, 2022)	germline	clinical testing	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	research
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing, curation
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Further Insights into the Ciliary Gene and Protein KIZ and Its Murine Ortholog PLK1S1 Mutated in Rod-Cone Dystrophy.

El Shamieh S, Méjécase C, Bertelli M, Terray A, Michiels C, Condroyer C, Fouquet S, Sadoun M, Clérin E, Liu B, Léveillard T, Goureau O, Sahel JA, Audo I, Zeitz C.

Genes (Basel). 2017 Oct 18;8(10). doi:pii: E277. 10.3390/genes8100277.

PubMed [citation]

PMID:: 29057815
PMCID:: PMC5664127

Whole Genome Sequencing Revealed Mutations in Two Independent Genes as the Underlying Cause of Retinal Degeneration in an Ashkenazi Jewish Pedigree.

Gustafson K, Duncan JL, Biswas P, Soto-Hermida A, Matsui H, Jakubosky D, Suk J, Telenti A, Frazer KA, Ayyagari R.

Genes (Basel). 2017 Aug 24;8(9). doi:pii: E210. 10.3390/genes8090210. Erratum in: Genes (Basel). 2017 Oct 23;8(10 ):.

PubMed [citation]

PMID:: 28837078
PMCID:: PMC5615344

See all PubMed Citations (6)

Details of each submission

From OMIM, SCV000150117.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (1)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Reproductive Health Research and Development, BGI Genomics, SCV001142495.1

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

Description

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.

#	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 Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard, SCV001445951.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	curation	PubMed (5)

Description

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).

#	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 Ocular Genomics Institute, Massachusetts Eye and Ear, SCV001573450.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	research	PubMed (6)

Description

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.

#	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 Fulgent Genetics, Fulgent Genetics, SCV002813808.1

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

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV003818832.2

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

#	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

Last Updated: Mar 30, 2024

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