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NM_014336.5(AIPL1):c.265T>C (p.Cys89Arg) AND Leber congenital amaurosis 4

Germline classification:
Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:
Jan 8, 2024
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:
RCV000696451.10

Allele description [Variation Report for NM_014336.5(AIPL1):c.265T>C (p.Cys89Arg)]

NM_014336.5(AIPL1):c.265T>C (p.Cys89Arg)

Gene:
AIPL1:aryl hydrocarbon receptor interacting protein like 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17p13.2
Genomic location:
Preferred name:
NM_014336.5(AIPL1):c.265T>C (p.Cys89Arg)
HGVS:
  • NC_000017.11:g.6433930A>G
  • NG_008474.1:g.6270T>C
  • NM_001033054.3:c.265T>C
  • NM_001033055.3:c.96+1079T>C
  • NM_001285399.3:c.229T>C
  • NM_001285400.3:c.199T>C
  • NM_001285401.3:c.265T>C
  • NM_001285402.2:c.148T>C
  • NM_001285403.4:c.265T>C
  • NM_014336.5:c.265T>CMANE SELECT
  • NP_001028226.1:p.Cys89Arg
  • NP_001272328.1:p.Cys77Arg
  • NP_001272329.1:p.Cys67Arg
  • NP_001272330.1:p.Cys89Arg
  • NP_001272331.1:p.Cys50Arg
  • NP_001272332.1:p.Cys89Arg
  • NP_055151.3:p.Cys89Arg
  • NC_000017.10:g.6337250A>G
  • NM_014336.4:c.265T>C
Protein change:
C50R
Links:
dbSNP: rs1264794214
NCBI 1000 Genomes Browser:
rs1264794214
Molecular consequence:
  • NM_001033055.3:c.96+1079T>C - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001033054.3:c.265T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285399.3:c.229T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285400.3:c.199T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285401.3:c.265T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285402.2:c.148T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285403.4:c.265T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014336.5:c.265T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
1

Condition(s)

Name:
Leber congenital amaurosis 4 (LCA4)
Synonyms:
Amaurosis congenita of Leber, type 4
Identifiers:
MONDO: MONDO:0011458; MedGen: C1858386; OMIM: 604393

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000825014Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 8, 2024)
germlineclinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV004045921Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
criteria provided, single submitter

(Classification criteria August 2017)
Likely pathogenic
(Aug 24, 2022)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes1not providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Interaction of aryl hydrocarbon receptor-interacting protein-like 1 with the farnesyl moiety.

Majumder A, Gopalakrishna KN, Cheguru P, Gakhar L, Artemyev NO.

J Biol Chem. 2013 Jul 19;288(29):21320-21328. doi: 10.1074/jbc.M113.476242. Epub 2013 Jun 4.

PubMed [citation]
PMID:
23737531
PMCID:
PMC3774400

Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client.

Gopalakrishna KN, Boyd K, Yadav RP, Artemyev NO.

J Biol Chem. 2016 Jul 29;291(31):16282-91. doi: 10.1074/jbc.M116.737593. Epub 2016 Jun 7.

PubMed [citation]
PMID:
27268253
PMCID:
PMC4965576
See all PubMed Citations (6)

Details of each submission

From Invitae, SCV000825014.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (5)

Description

This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 89 of the AIPL1 protein (p.Cys89Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Leber congenital amaurosis (PMID: 20702822; Invitae). ClinVar contains an entry for this variant (Variation ID: 574505). 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 expected to disrupt AIPL1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects AIPL1 function (PMID: 23737531, 27268253, 28973376). This variant disrupts the p.Cys89 amino acid residue in AIPL1. Other variant(s) that disrupt this residue have been observed in individuals with AIPL1-related conditions (PMID: 20702822), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV004045921.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided1not providednot providednot provided

Last Updated: Jun 23, 2024