NM_000350.3(ABCA4):c.3352C>T (p.His1118Tyr) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 20, 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:: RCV001235193.10

Allele description [Variation Report for NM_000350.3(ABCA4):c.3352C>T (p.His1118Tyr)]

NM_000350.3(ABCA4):c.3352C>T (p.His1118Tyr)

Gene:

ABCA4:ATP binding cassette subfamily A member 4 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p22.1

Genomic location:

Preferred name:

NM_000350.3(ABCA4):c.3352C>T (p.His1118Tyr)

HGVS:

NC_000001.11:g.94041379G>A
NG_009073.1:g.84771C>T
NG_009073.2:g.84769C>T
NM_000350.3:c.3352C>TMANE SELECT
NM_001425324.1:c.3130C>T
NP_000341.2:p.His1118Tyr
NP_001412253.1:p.His1044Tyr
NC_000001.10:g.94506935G>A
NM_000350.2:c.3352C>T

Protein change:

H1044Y

Links:

dbSNP: rs369440533

NCBI 1000 Genomes Browser:

rs369440533

Molecular consequence:

NM_000350.3:c.3352C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.3130C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001407869	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 20, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26551331, 30029497, 25472526, 28559085, 28492532
SCV001764370	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Dec 1, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001407869

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 20, 2024)

germline

clinical testing

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

SCV001764370

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Dec 1, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

Citations

PubMed

Quantitative Fundus Autofluorescence and Optical Coherence Tomography in ABCA4 Carriers.

Duncker T, Stein GE, Lee W, Tsang SH, Zernant J, Bearelly S, Hood DC, Greenstein VC, Delori FC, Allikmets R, Sparrow JR.

Invest Ophthalmol Vis Sci. 2015 Nov;56(12):7274-85. doi: 10.1167/iovs.15-17371.

PubMed [citation]

PMID:: 26551331
PMCID:: PMC4642605

Application of Whole Exome and Targeted Panel Sequencing in the Clinical Molecular Diagnosis of 319 Chinese Families with Inherited Retinal Dystrophy and Comparison Study.

Wang L, Zhang J, Chen N, Wang L, Zhang F, Ma Z, Li G, Yang L.

Genes (Basel). 2018 Jul 19;9(7). doi:pii: E360. 10.3390/genes9070360.

PubMed [citation]

PMID:: 30029497
PMCID:: PMC6071067

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001407869.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1118 of the ABCA4 protein (p.His1118Tyr). This variant is present in population databases (rs369440533, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of Stargardt disease and inherited retinal dystrophy (PMID: 26551331, 30029497; Invitae). ClinVar contains an entry for this variant (Variation ID: 961495). 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 ABCA4 protein function with a positive predictive value of 95%. This variant disrupts the p.His1118 amino acid residue in ABCA4. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 25472526, 28559085). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

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

From GeneDx, SCV001764370.2

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30029497, 26551331, 34954332, 37108442, 33090715, 33261146, 34945039)

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

Last Updated: Sep 29, 2024

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