VCV000001009.18 - ClinVar

NM_001031710.3(KLHL7):c.458C>T (p.Ala153Val)

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.

(10)

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_001031710.3(KLHL7):c.458C>T (p.Ala153Val)

Variation ID: 1009 Accession: VCV000001009.18

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 7p15.3 7: 23140784 (GRCh38) [ NCBI UCSC ] 7: 23180403 (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	Apr 4, 2013	Dec 28, 2024	Dec 13, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001031710.3:c.458C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001026880.2:p.Ala153Val	missense
NM_018846.5:c.314C>T	NP_061334.4:p.Ala105Val	missense
NR_033328.2:n.831C>T		non-coding transcript variant
NC_000007.14:g.23140784C>T
NC_000007.13:g.23180403C>T
NG_016983.2:g.40051C>T
	Q8IXQ5:p.Ala153Val

... more HGVS ... less HGVS

Protein change

A153V, A105V

Other names

Canonical SPDI

NC_000007.14:23140783: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.

Links

ClinGen: CA221427 UniProtKB: Q8IXQ5#VAR_060674 OMIM: 611119.0002 dbSNP: rs137853113 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.
KLHL7		-	-	GRCh38 GRCh37	363	399

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 42	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Apr 29, 2021	RCV000001064.12
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 13, 2023	RCV000079374.23
Retinitis pigmentosa	Likely pathogenic (1)	no assertion criteria provided	Jun 23, 2019	RCV001003071.9
Retinal dystrophy	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV001073803.12

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 (Aug 16, 2013)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000111244.8 First in ClinVar: Jan 17, 2014 Last updated: Jun 29, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KLHL7 Number of individuals with the variant: 1 Zygosity: Single Heterozygote Sex: mixed
Pathogenic (Apr 11, 2018)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239365.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Pathogenic (Mar 04, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 42 Affected status: yes Allele origin: germline	Institute of Human Genetics, University of Leipzig Medical Center Accession: SCV001428729.1 First in ClinVar: Aug 17, 2020 Last updated: Aug 17, 2020	Number of individuals with the variant: 1
Pathogenic (Jun 17, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen Accession: SCV001762021.1 First in ClinVar: Jul 31, 2021 Last updated: Jul 31, 2021	Clinical Features: Rod-cone dystrophy (present) Sex: female
Pathogenic (Apr 29, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinitis pigmentosa 42 Affected status: yes Allele origin: germline	Genetics and Molecular Pathology, SA Pathology Additional submitter: Shariant Australia, Australian Genomics Accession: SCV002761630.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022
Pathogenic (Dec 13, 2023)	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: SCV001397681.5 First in ClinVar: Jul 16, 2020 Last updated: Feb 14, 2024	Publications: PubMed (2) PubMed: 19520207‚ 21828050 Comment: This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 153 of the KLHL7 protein (p.Ala153Val). … (more) This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 153 of the KLHL7 protein (p.Ala153Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 19520207). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1009). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KLHL7 function (PMID: 21828050). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (Submitter's publication) Method: research	Retinal dystrophy Affected status: yes Allele origin: germline	Dept Of Ophthalmology, Nagoya University Accession: SCV004704743.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Pathogenic (Jan 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg Accession: SCV005072536.1 First in ClinVar: Dec 28, 2024 Last updated: Dec 28, 2024	Publications: PubMed (10) PubMed: 19520207‚ 20547956‚ 21828050‚ 28559085‚ 31856884‚ 31456290‚ 33576794‚ 35052694‚ 36460718‚ 36819107
Pathogenic (Sep 23, 2011)	no assertion criteria provided Method: literature only	RETINITIS PIGMENTOSA 42 Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021214.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (2) PubMed: 19520207‚ 21828050 Comment on evidence: In affected members of 3 unrelated families from Scandinavia, North America, and the U.K. with autosomal dominant retinitis pigmentosa (RP42; 612943), Friedman et al. (2009) … (more) In affected members of 3 unrelated families from Scandinavia, North America, and the U.K. with autosomal dominant retinitis pigmentosa (RP42; 612943), Friedman et al. (2009) identified a 458C-T transition in exon 6 of the KLHL7 gene, resulting in an ala153-to-val (A153V) substitution at a highly conserved residue. The mutation was not found in 102 Scandinavian, 183 North American, or 185 U.K. controls. Kigoshi et al. (2011) showed that the A153V substitution abrogated interaction and colocalization of KLHL7 with CUL3 (603136). KLHL7 with A153V could form heterodimers with wildtype KLHL7 and did not interfere with interaction between wildtype KLHL7 and CUL3. However, inclusion of KLHL7 with A153V reduced the apparent E3 ligase activity of the wildtype KLHL7-CUL3 complex. (less)
Likely 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: SCV001161128.1 First in ClinVar: Feb 16, 2020 Last updated: Feb 16, 2020

Comment:

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 153 of the KLHL7 protein (p.Ala153Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant retinitis pigmentosa (PMID: 19520207). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1009). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects KLHL7 function (PMID: 21828050). For these reasons, this variant has been classified as Pathogenic.

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
Cost-effective sequence analysis of 113 genes in 1,192 probands with retinitis pigmentosa and Leber congenital amaurosis.	Panneman DM	Frontiers in cell and developmental biology	2023	PMID: 36819107
Genetic epidemiology of inherited retinal diseases in a large patient cohort followed at a single center in Italy.	Karali M	Scientific reports	2022	PMID: 36460718
There Is More Than Meets the Eye: Identification of Dual Molecular Diagnosis in Patients Affected by Hearing Loss.	Morgan A	Biomedicines	2021	PMID: 35052694
Molecular Epidemiology in 591 Italian Probands With Nonsyndromic Retinitis Pigmentosa and Usher Syndrome.	Colombo L	Investigative ophthalmology & visual science	2021	PMID: 33576794
A nationwide genetic analysis of inherited retinal diseases in Israel as assessed by the Israeli inherited retinal disease consortium (IIRDC).	Sharon D	Human mutation	2020	PMID: 31456290
Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa.	Oh JK	Orphanet journal of rare diseases	2019	PMID: 31856884
Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.	Stone EM	Ophthalmology	2017	PMID: 28559085
Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation.	Kigoshi Y	The Journal of biological chemistry	2011	PMID: 21828050
Phenotype associated with mutation in the recently identified autosomal dominant retinitis pigmentosa KLHL7 gene.	Hugosson T	Archives of ophthalmology (Chicago, Ill. : 1960)	2010	PMID: 20547956
Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa.	Friedman JS	American journal of human genetics	2009	PMID: 19520207
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=KLHL7	-	-	-	-
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Text-mined citations for rs137853113 ...

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 Jan 26, 2025

ClinVar Genomic variation as it relates to human health

NM_001031710.3(KLHL7):c.458C>T (p.Ala153Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs137853113 ...