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NM_014336.5(AIPL1):c.377T>A (p.Met126Lys) AND Leber congenital amaurosis 4

Germline classification:
Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:
Jan 19, 2024
Review status:
criteria provided, conflicting classifications
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:
RCV000343358.9

Allele description [Variation Report for NM_014336.5(AIPL1):c.377T>A (p.Met126Lys)]

NM_014336.5(AIPL1):c.377T>A (p.Met126Lys)

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.377T>A (p.Met126Lys)
HGVS:
  • NC_000017.11:g.6428406A>T
  • NG_008474.1:g.11794T>A
  • NM_001033054.3:c.277-1349T>A
  • NM_001033055.3:c.197T>A
  • NM_001285399.3:c.341T>A
  • NM_001285400.3:c.311T>A
  • NM_001285401.3:c.377T>A
  • NM_001285402.2:c.260T>A
  • NM_001285403.4:c.377T>A
  • NM_014336.4:c.377T>A
  • NM_014336.5:c.377T>AMANE SELECT
  • NP_001028227.1:p.Met66Lys
  • NP_001272328.1:p.Met114Lys
  • NP_001272329.1:p.Met104Lys
  • NP_001272330.1:p.Met126Lys
  • NP_001272331.1:p.Met87Lys
  • NP_001272332.1:p.Met126Lys
  • NP_055151.3:p.Met126Lys
  • NC_000017.10:g.6331726A>T
  • NM_014336.3:c.377T>A
Protein change:
M104K
Links:
dbSNP: rs761622978
NCBI 1000 Genomes Browser:
rs761622978
Molecular consequence:
  • NM_001033054.3:c.277-1349T>A - intron variant - [Sequence Ontology: SO:0001627]
  • NM_001033055.3:c.197T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285399.3:c.341T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285400.3:c.311T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285401.3:c.377T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285402.2:c.260T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001285403.4:c.377T>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_014336.5:c.377T>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV000405609Illumina Laboratory Services, Illumina
criteria provided, single submitter

(ICSL Variant Classification Criteria 13 December 2019)
Uncertain significance
(Jan 12, 2018)
germlineclinical testing

Citation Link,

SCV002274127Invitae
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 19, 2024)
germlineclinical testing

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

Summary from all submissions

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

Citations

PubMed

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]
PMID:
28492532
PMCID:
PMC5632818

Details of each submission

From Illumina Laboratory Services, Illumina, SCV000405609.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

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

From Invitae, SCV002274127.3

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

Description

This sequence change replaces methionine, which is neutral and non-polar, with lysine, which is basic and polar, at codon 126 of the AIPL1 protein (p.Met126Lys). This variant is present in population databases (rs761622978, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of inherited retinal dystrophy (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: 324620). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on AIPL1 protein function. For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Jun 23, 2024