NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser) AND Leber congenital amaurosis 2

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Dec 30, 2023
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:: RCV000986328.5

Allele description [Variation Report for NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)]

NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)

Gene:

RPE65:retinoid isomerohydrolase RPE65 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p31.3

Genomic location:

Preferred name:

NM_000329.3(RPE65):c.1022T>C (p.Leu341Ser)

Other names:

NP_000320.1:p.(Leu341Ser); NM_000329.3(RPE65):c.1022T>C

HGVS:

NC_000001.11:g.68438293A>G
NG_008472.2:g.16667T>C
NM_000329.3:c.1022T>CMANE SELECT
NP_000320.1:p.Leu341Ser
NC_000001.10:g.68903976A>G
NG_008472.1:g.16667T>C
NM_000329.2:c.1022T>C
Q16518:p.Leu341Ser

Protein change:

L341S; LEU341SER

Links:

UniProtKB: Q16518#VAR_017137; OMIM: 180069.0004; dbSNP: rs61752909

NCBI 1000 Genomes Browser:

rs61752909

Molecular consequence:

NM_000329.3:c.1022T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Leber congenital amaurosis 2 (LCA2)
Synonyms:: AMAUROSIS CONGENITA OF LEBER II; Amaurosis congenita of Leber, type 2; RPE65-Related Leber Congenital Amaurosis
Identifiers:: MONDO: MONDO:0008765; MedGen: C1859844; Orphanet: 65; OMIM: 204100

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RNA polymerase subunit 1 [African swine fever virus]
RNA polymerase subunit 1 [African swine fever virus]
gi|723633597|gb|AIY22448.1|

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001135301	Mendelics	criteria provided, single submitter (Mendelics Assertion Criteria 2017)	Pathogenic (May 28, 2019)	unknown	clinical testing	Citation Link,
SCV001425565	Laboratory of Genetics in Ophthalmology, Institut Imagine	no assertion criteria provided	Pathogenic	inherited	research	PubMed (1) [See all records that cite this PMID]
SCV002521281	3billion	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (May 22, 2022)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 9501220, 20079931, 25741868
SCV004209209	Baylor Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Dec 30, 2023)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	inherited	yes	1	not provided	not provided	not provided	not provided	research
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.

Morimura H, Fishman GA, Grover SA, Fulton AB, Berson EL, Dryja TP.

Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):3088-93.

PubMed [citation]

PMID:: 9501220
PMCID:: PMC19699

Visual acuity in patients with Leber's congenital amaurosis and early childhood-onset retinitis pigmentosa.

Walia S, Fishman GA, Jacobson SG, Aleman TS, Koenekoop RK, Traboulsi EI, Weleber RG, Pennesi ME, Heon E, Drack A, Lam BL, Allikmets R, Stone EM.

Ophthalmology. 2010 Jun;117(6):1190-8. doi: 10.1016/j.ophtha.2009.09.056. Epub 2010 Jan 15.

PubMed [citation]

PMID:: 20079931

See all PubMed Citations (3)

Details of each submission

From Mendelics, SCV001135301.1

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

#	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 Laboratory of Genetics in Ophthalmology, Institut Imagine, SCV001425565.1

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

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

From 3billion, SCV002521281.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	PubMed (3)

Description

The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.88; 3Cnet: 0.98). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013118). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 20079931) and to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID:9501220). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.

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

From Baylor Genetics, SCV004209209.2

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 3, 2024

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