VCV000013119.34 - ClinVar

NM_000329.3(RPE65):c.394G>A (p.Ala132Thr)

Germline

Top reviewed classifications are shown here.

Submission summary:

13 submissions

13 submitters

8 conditions

Reviewed by expert panel

Benign

Dec 2023 by ClinGen Leber … FDA Recognized Database

for RPE65-related recessive retinopathy

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000329.3(RPE65):c.394G>A (p.Ala132Thr)

Variation ID: 13119 Accession: VCV000013119.34

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.3 1: 68444632 (GRCh38) [ NCBI UCSC ] 1: 68910315 (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	Feb 20, 2014	Oct 20, 2024	Dec 22, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_000329.3:c.394G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000320.1:p.Ala132Thr	missense
NC_000001.11:g.68444632C>T
NC_000001.10:g.68910315C>T
NG_008472.2:g.10328G>A
	Q16518:p.Ala132Thr

... more HGVS ... less HGVS

Protein change

A132T

Other names

NM_000329.3(RPE65):c.394G>A

Canonical SPDI

NC_000001.11:68444631: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.

0.00339 (T)

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

Exome Aggregation Consortium (ExAC) 0.00287

The Genome Aggregation Database (gnomAD), exomes 0.00294

1000 Genomes Project 30x 0.00297

1000 Genomes Project 0.00339

The Genome Aggregation Database (gnomAD) 0.00103

Trans-Omics for Precision Medicine (TOPMed) 0.00112

Links

OMIM: 180069.0005 dbSNP: rs61752878 ClinGen: CA226547 UniProtKB: Q16518#VAR_017132 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.
RPE65		-	-	GRCh38 GRCh37	957	983

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 20	Uncertain significance (1)	no assertion criteria provided	Mar 17, 1998	RCV000013998.32
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Aug 1, 2024	RCV000085196.25
Leber congenital amaurosis 2	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	Aug 22, 2023	RCV000986331.15
Leber congenital amaurosis 2 Retinitis pigmentosa 20	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000665910.17
Leber congenital amaurosis	Uncertain significance (1)	no assertion criteria provided	Apr 3, 2020	RCV001278137.9
not specified	Likely benign (1)	criteria provided, single submitter	May 3, 2022	RCV002265555.8
RPE65-related recessive retinopathy	Benign (1)	reviewed by expert panel	Dec 22, 2023	RCV003460469.1
RPE65-related disorder	Benign (1)	no assertion criteria provided	Sep 10, 2024	RCV004732543.1

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.
Benign (Dec 22, 2023)	reviewed by expert panel (ClinGen LCAeoRD ACMG Specifications RPE65 V1.0.0) Method: curation	RPE65-related recessive retinopathy (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	ClinGen Leber Congenital Amaurosis/early Onset Retinal Dystrophy Variant Curation Expert Panel, ClinGen FDA Recognized Database Accession: SCV004190214.1 First in ClinVar: Dec 30, 2023 Last updated: Dec 30, 2023	Publications: PubMed (1) PubMed: 16150724 Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c96cbaae-09fb-4a90-9c7a-dcd5435fd7ff Comment: NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency … (more) NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01113, with 372 alleles / 30614 total alleles in the South Asian population (with 6 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The computational predictor REVEL gives a score of 0.548, which is above the ClinGen LCA / eoRD VCEP threshold of <0.3 and does not strongly predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a score of 0.03 for splice acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of greater than or equal to 0.2 and does not strongly predict an impact on splicing. The variant exhibited 50% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves] normal protein function (PMID: 16150724, BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
Likely benign (Mar 06, 2017)	criteria provided, single submitter (Counsyl Autosomal Recessive and X-Linked Classification Criteria (2018)) Method: clinical testing	Leber congenital amaurosis 2 Retinitis pigmentosa 20 Affected status: unknown Allele origin: unknown	Counsyl Accession: SCV000790116.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (1) PubMed: 16150724
Likely benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Leber congenital amaurosis 2 (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard Accession: SCV001435229.1 First in ClinVar: Oct 03, 2020 Last updated: Oct 03, 2020	Publications: PubMed (4) PubMed: 9501220‚ 16150724‚ 24066033‚ 24265693 Comment: The p.Ala132Thr variant in RPE65 has been identified in 2 homozygous siblings from 1 family with retinitis pigmentosa (PMID: 9501220), and in the heterozygous state … (more) The p.Ala132Thr variant in RPE65 has been identified in 2 homozygous siblings from 1 family with retinitis pigmentosa (PMID: 9501220), and in the heterozygous state in 2 unrelated individuals with retinitis pigmentosa from India and Dubai respectively (PMID: 24066033, 24265693). In vitro functional studies provide some evidence that the p.Ala132Thr variant may slightly impact protein function (PMID: 16150724). However, these types of assays may not accurately represent biological function and this variant has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive retinitis pigmentosa. (less)
Likely benign (Feb 05, 2018)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000565494.5 First in ClinVar: Apr 29, 2017 Last updated: Mar 04, 2023	Comment: This variant is associated with the following publications: (PMID: 18722466, 21931134, 11095629, 16150724, 24066033, 9501220, 27535533, 26355662, 26626312)
Benign (Aug 22, 2023)	criteria provided, single submitter (Mendelics Assertion Criteria 2019) Method: clinical testing	Leber congenital amaurosis 2 Affected status: unknown Allele origin: germline	Mendelics Accession: SCV001135304.2 First in ClinVar: Jan 09, 2020 Last updated: Aug 25, 2023
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Leber congenital amaurosis 2 Retinitis pigmentosa 20 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. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001091443.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Benign (Aug 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV003916464.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: RPE65: BS1, BS2 Number of individuals with the variant: 30
Likely benign (Jun 10, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Leber congenital amaurosis 2 Affected status: no Allele origin: germline	Genome-Nilou Lab Accession: SCV001737261.1 First in ClinVar: Jun 19, 2021 Last updated: Jun 19, 2021	Sex: mixed
Likely benign (May 03, 2022)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV002547977.1 First in ClinVar: Jul 18, 2022 Last updated: Jul 18, 2022
Uncertain significance (Mar 17, 1998)	no assertion criteria provided Method: literature only	RECLASSIFIED - VARIANT OF UNKNOWN SIGNIFICANCE Affected status: not provided Allele origin: germline	OMIM Accession: SCV000034245.2 First in ClinVar: Apr 04, 2013 Last updated: Oct 11, 2015	Publications: PubMed (2) PubMed: 27535533‚ 9501220 Comment on evidence: This variant, formerly titled RETINITIS PIGMENTOSA 20, has been reclassified based on the report of Lek et al. (2016). In a brother and sister with … (more) This variant, formerly titled RETINITIS PIGMENTOSA 20, has been reclassified based on the report of Lek et al. (2016). In a brother and sister with retinitis pigmentosa (RP20; 613794), Morimura et al. (1998) observed an ala132-to-thr (A132T) mutation in the RPE65 gene in homozygous state. Lek et al. (2016) found the A132T variant in homozygosity in 4 individuals in the ExAC database and noted that it had a high allele frequency (0.0128) in South Asians, suggesting that it is not pathogenic. (less)
Uncertain significance (Apr 03, 2020)	no assertion criteria provided Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001465133.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021
Benign (Sep 10, 2024)	no assertion criteria provided Method: clinical testing	RPE65-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV005352246.1 First in ClinVar: Oct 08, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	Retina International Accession: SCV000117333.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_RPE65:c.394G>A
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Comment:

NM_000329.3(RPE65):c.394G>A is a missense variant that replaces alanine with threonine at codon 132. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.01113, with 372 alleles / 30614 total alleles in the South Asian population (with 6 homozygotes), which is higher than the ClinGen LCA / eoRD VCEP BA1 threshold of >0.008 (BA1). The computational predictor REVEL gives a score of 0.548, which is above the ClinGen LCA / eoRD VCEP threshold of <0.3 and does not strongly predict a non-damaging effect on RPE65 function. The splicing impact predictor SpliceAI gives a score of 0.03 for splice acceptor loss, which is below the ClinGen LCA / eoRD VCEP recommended threshold of greater than or equal to 0.2 and does not strongly predict an impact on splicing. The variant exhibited 50% enzymatic activity in an isomerohydrolase assay relative to the wild-type control, which is higher than the ClinGen LCA / eoRD BS3_Supporting threshold of >50% activity, indicating that it largely preserves] normal protein function (PMID: 16150724, BS3_Supporting). In summary, this variant meets the criteria to be classified as benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BA1, BS3_Supporting. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Comment:

The p.Ala132Thr variant in RPE65 has been identified in 2 homozygous siblings from 1 family with retinitis pigmentosa (PMID: 9501220), and in the heterozygous state in 2 unrelated individuals with retinitis pigmentosa from India and Dubai respectively (PMID: 24066033, 24265693). In vitro functional studies provide some evidence that the p.Ala132Thr variant may slightly impact protein function (PMID: 16150724). However, these types of assays may not accurately represent biological function and this variant has been identified in >1% of South Asian chromosomes and 4 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely benign for autosomal recessive retinitis pigmentosa.

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
Analysis of protein-coding genetic variation in 60,706 humans.	Lek M	Nature	2016	PMID: 27535533
Increasing the yield in targeted next-generation sequencing by implicating CNV analysis, non-coding exons and the overall variant load: the example of retinal dystrophies.	Eisenberger T	PloS one	2013	PMID: 24265693
Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients.	Verma A	PloS one	2013	PMID: 24066033
Mutation of key residues of RPE65 abolishes its enzymatic role as isomerohydrolase in the visual cycle.	Redmond TM	Proceedings of the National Academy of Sciences of the United States of America	2005	PMID: 16150724
Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.	Morimura H	Proceedings of the National Academy of Sciences of the United States of America	1998	PMID: 9501220
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/c96cbaae-09fb-4a90-9c7a-dcd5435fd7ff	-	-	-	-

Text-mined citations for rs61752878 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000329.3(RPE65):c.394G>A (p.Ala132Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61752878 ...