VCV000098903.23 - ClinVar

NM_000329.3(RPE65):c.978G>T (p.Val326=)

Germline

Top reviewed classifications are shown here.

Submission summary:

9 submissions

8 submitters

6 conditions

Reviewed by expert panel

Likely Benign

Apr 2024 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.978G>T (p.Val326=)

Variation ID: 98903 Accession: VCV000098903.23

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.3 1: 68438962 (GRCh38) [ NCBI UCSC ] 1: 68904645 (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	Apr 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000329.3:c.978G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000320.1:p.Val326=	synonymous
NC_000001.11:g.68438962C>A
NC_000001.10:g.68904645C>A
NG_008472.2:g.15998G>T

Protein change

Other names

NM_000329.3(RPE65):c.978G>T
p.Val326=

Canonical SPDI

NC_000001.11:68438961:C: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.

0.00240 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00057

Exome Aggregation Consortium (ExAC) 0.00068

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00161

The Genome Aggregation Database (gnomAD) 0.00186

Trans-Omics for Precision Medicine (TOPMed) 0.00193

1000 Genomes Project 0.00240

1000 Genomes Project 30x 0.00281

Links

ClinGen: CA226597 dbSNP: rs61752907 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.
not provided	Benign/Likely benign (3)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000085236.10
not specified	Likely benign (1)	criteria provided, single submitter	Aug 23, 2016	RCV000261103.4
Leber congenital amaurosis 2 Retinitis pigmentosa 20	Benign/Likely benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV000671895.8
Leber congenital amaurosis 2	Uncertain significance (1)	criteria provided, single submitter	Dec 28, 2017	RCV001100476.4
Retinitis pigmentosa	Likely benign (1)	criteria provided, single submitter	Dec 28, 2017	RCV001100477.4
RPE65-related recessive retinopathy	Likely benign (1)	reviewed by expert panel	Apr 22, 2024	RCV004527322.1

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.
Likely Benign (Apr 22, 2024)	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: SCV005038786.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/01fe12a6-ad99-41bd-8c57-2461b36468ac Comment: The variant NM_000329.3(RPE65):c.978G>T, p.Val326= is a synonymous (silent) variant in exon 9. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of … (more) The variant NM_000329.3(RPE65):c.978G>T, p.Val326= is a synonymous (silent) variant in exon 9. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.004399, with 376 alleles/74964 total alleles in the African/African American population, which is greater than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
Likely benign (Jan 04, 2018)	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: SCV000796928.1 First in ClinVar: Aug 05, 2018 Last updated: Aug 05, 2018	Publications: PubMed (3) PubMed: 17964524‚ 9501220‚ 18722466
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001886309.1 First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021
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: SCV001021570.5 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Likely benign (May 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: SCV005050722.5 First in ClinVar: Jun 17, 2024 Last updated: Oct 20, 2024	Comment: RPE65: BP4, BP7 Number of individuals with the variant: 1
Likely benign (Aug 23, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000343539.4 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RPE65 http://www.ncbi.nlm.nih.gov/vari… http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=1&from=68904645&to=68904645 Number of individuals with the variant: 1 Sex: mixed
Likely benign (Dec 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Retinitis pigmentosa Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001256999.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 18722466‚ 14971589‚ 9501220 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Uncertain significance (Dec 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Leber congenital amaurosis 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001256998.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Publications: PubMed (3) PubMed: 14971589‚ 9501220‚ 18722466 Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000117373.1 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.978G>T

Comment:

The variant NM_000329.3(RPE65):c.978G>T, p.Val326= is a synonymous (silent) variant in exon 9. This variant is present in gnomAD v.4.0.0 at a GrpMax allele frequency of 0.004399, with 376 alleles/74964 total alleles in the African/African American population, which is greater than the ClinGen LCA/eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.02, which is below the ClinGen LCA/eoRD VCEP recommended threshold of <0.1 and does not predict an impact on splicing (BP4, BP7). In summary, this variant meets the criteria to be classified as likely benign for RPE65-related recessive retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen LCA/eoRD VCEP: BS1, BP4, BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023).

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Impact of retinal disease-associated RPE65 mutations on retinoid isomerization.	Bereta G	Biochemistry	2008	PMID: 18722466
Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.	Stone EM	American journal of ophthalmology	2007	PMID: 17964524
Finding and interpreting genetic variations that are important to ophthalmologists.	Stone EM	Transactions of the American Ophthalmological Society	2003	PMID: 14971589
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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=RPE65	-	-	-	-
http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=1&from=68904645&to=68904645	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/01fe12a6-ad99-41bd-8c57-2461b36468ac	-	-	-	-

Text-mined citations for rs61752907 ...

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 Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_000329.3(RPE65):c.978G>T (p.Val326=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61752907 ...