VCV000716567.15 - ClinVar

NM_000329.3(RPE65):c.441A>G (p.Thr147=)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

5 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.441A>G (p.Thr147=)

Variation ID: 716567 Accession: VCV000716567.15

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p31.3 1: 68444585 (GRCh38) [ NCBI UCSC ] 1: 68910268 (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	Dec 17, 2019	May 7, 2024	Apr 22, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000329.3:c.441A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000320.1:p.Thr147=	synonymous
NC_000001.11:g.68444585T>C
NC_000001.10:g.68910268T>C
NG_008472.2:g.10375A>G

Protein change

Other names

NM_000329.3(RPE65):c.441A>G
p.Thr147=

Canonical SPDI

NC_000001.11:68444584:T:C

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.

0.00100 (C)

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

The Genome Aggregation Database (gnomAD) 0.00012

Trans-Omics for Precision Medicine (TOPMed) 0.00023

The Genome Aggregation Database (gnomAD), exomes 0.00054

Exome Aggregation Consortium (ExAC) 0.00064

1000 Genomes Project 30x 0.00078

1000 Genomes Project 0.00100

Links

dbSNP: rs185049543 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	Uncertain significance (1)	criteria provided, single submitter	Apr 28, 2017	RCV001102521.4
Leber congenital amaurosis 2	Likely benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV001102522.4
Leber congenital amaurosis	Benign (1)	no assertion criteria provided	Nov 11, 2019	RCV001275286.1
Leber congenital amaurosis 2 Retinitis pigmentosa 20	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV000889235.9
RPE65-related recessive retinopathy	Likely benign (1)	reviewed by expert panel	Apr 22, 2024	RCV004527401.1
Retinal dystrophy	Likely benign (1)	criteria provided, single submitter	Oct 1, 2023	RCV003890018.1

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: SCV005038770.1 First in ClinVar: May 07, 2024 Last updated: May 07, 2024	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ad6cdaf9-6645-4a76-8fb6-68346a72c8aa Comment: NM_000329.3(RPE65):c.441A>C (p.Thr147=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.006282, with … (more) NM_000329.3(RPE65):c.441A>C (p.Thr147=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.006282, with 142 alleles/19954 total alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.05 for donor gain, 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, and BP7. (VCEP specifications version 1.0.0; date of approval 09/21/2023). (less)
Uncertain significance (Apr 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: SCV001259199.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. (less)
Likely benign (Apr 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: SCV001259200.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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: SCV001032902.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 28, 2024
Likely benign (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: SCV004706385.1 First in ClinVar: Mar 10, 2024 Last updated: Mar 10, 2024
Benign (Nov 11, 2019)	no assertion criteria provided Method: clinical testing	Leber congenital amaurosis Affected status: unknown Allele origin: germline	Natera, Inc. Accession: SCV001460286.1 First in ClinVar: Jan 02, 2021 Last updated: Jan 02, 2021

Comment:

NM_000329.3(RPE65):c.441A>C (p.Thr147=) is a synonymous variant located in exon 5. This variant is present in gnomAD v.2.1.1 at a GrpMax allele frequency of 0.006282, with 142 alleles/19954 total alleles in the East Asian population, which is higher than the ClinGen LCA / eoRD VCEP BS1 threshold of >0.0008 (BS1). The splicing impact predictor SpliceAI gives a delta score of 0.05 for donor gain, 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, and 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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ad6cdaf9-6645-4a76-8fb6-68346a72c8aa	-	-	-	-

Text-mined citations for rs185049543 ...

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_000329.3(RPE65):c.441A>G (p.Thr147=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs185049543 ...