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NM_000329.3(RPE65):c.484A>C (p.Thr162Pro) AND multiple conditions

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Dec 29, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
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:
RCV001206190.6

Allele description [Variation Report for NM_000329.3(RPE65):c.484A>C (p.Thr162Pro)]

NM_000329.3(RPE65):c.484A>C (p.Thr162Pro)

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.484A>C (p.Thr162Pro)
HGVS:
  • NC_000001.11:g.68444542T>G
  • NG_008472.2:g.10418A>C
  • NM_000329.3:c.484A>CMANE SELECT
  • NP_000320.1:p.Thr162Pro
  • NC_000001.10:g.68910225T>G
  • NG_008472.1:g.10418A>C
  • NM_000329.2:c.484A>C
Protein change:
T162P
Links:
dbSNP: rs774309607
NCBI 1000 Genomes Browser:
rs774309607
Molecular consequence:
  • NM_000329.3:c.484A>C - missense variant - [Sequence Ontology: SO:0001583]

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
Name:
Retinitis pigmentosa 20 (RP20)
Synonyms:
RP 20
Identifiers:
MONDO: MONDO:0013425; MedGen: C3151086; Orphanet: 791; OMIM: 613794

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV001377487Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Likely pathogenic
(Dec 29, 2023)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Leber congenital amaurosis - a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture.

Stone EM.

Am J Ophthalmol. 2007 Dec;144(6):791-811. Epub 2007 Oct 26.

PubMed [citation]
PMID:
17964524

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001377487.5

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 162 of the RPE65 protein (p.Thr162Pro). This variant is present in population databases (rs774309607, gnomAD 0.002%). This missense change has been observed in individual(s) with Leber congenital amaurosis or retinitis pigmentosa (PMID: 17964524, 20079931; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 870346). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RPE65 protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024