NM_000350.3(ABCA4):c.1919C>T (p.Pro640Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (2 submissions)
Last evaluated:: Jan 25, 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:: RCV000439383.9

Allele description [Variation Report for NM_000350.3(ABCA4):c.1919C>T (p.Pro640Leu)]

NM_000350.3(ABCA4):c.1919C>T (p.Pro640Leu)

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.1919C>T (p.Pro640Leu)

HGVS:

NC_000001.11:g.94062595G>A
NG_009073.1:g.63555C>T
NG_009073.2:g.63553C>T
NM_000350.3:c.1919C>TMANE SELECT
NM_001425324.1:c.1919C>T
NP_000341.2:p.Pro640Leu
NP_001412253.1:p.Pro640Leu
NC_000001.10:g.94528151G>A
NM_000350.2:c.1919C>T

Protein change:

P640L

Links:

dbSNP: rs760790294

NCBI 1000 Genomes Browser:

rs760790294

Molecular consequence:

NM_000350.3:c.1919C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.1919C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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hypothetical protein, conserved [Trypanosoma cruzi]
hypothetical protein, conserved [Trypanosoma cruzi]
gi|71663452|ref|XP_818718.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000511884	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Likely pathogenic (Nov 2, 2021)	germline	clinical testing	Citation Link,
SCV002266620	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 20647261, 29925512, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000511884

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Likely pathogenic
(Nov 2, 2021)

germline

clinical testing

Citation Link,

SCV002266620

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 25, 2024)

germline

clinical testing

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

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

Deducing the pathogenic contribution of recessive ABCA4 alleles in an outbred population.

Schindler EI, Nylen EL, Ko AC, Affatigato LM, Heggen AC, Wang K, Sheffield VC, Stone EM.

Hum Mol Genet. 2010 Oct 1;19(19):3693-701. doi: 10.1093/hmg/ddq284. Epub 2010 Jul 20.

PubMed [citation]

PMID:: 20647261
PMCID:: PMC2935854

Detailed genetic characteristics of an international large cohort of patients with Stargardt disease: ProgStar study report 8.

Fujinami K, Strauss RW, Chiang JP, Audo IS, Bernstein PS, Birch DG, Bomotti SM, Cideciyan AV, Ervin AM, Marino MJ, Sahel JA, Mohand-Said S, Sunness JS, Traboulsi EI, West S, Wojciechowski R, Zrenner E, Michaelides M, Scholl HPN; ProgStar Study Group.; ProgStar Study Group..

Br J Ophthalmol. 2019 Mar;103(3):390-397. doi: 10.1136/bjophthalmol-2018-312064. Epub 2018 Jun 20.

PubMed [citation]

PMID:: 29925512
PMCID:: PMC6579578

See all PubMed Citations (3)

Details of each submission

From GeneDx, SCV000511884.6

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

Description

Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 20647261, 29925512)

#	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

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002266620.3

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

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 640 of the ABCA4 protein (p.Pro640Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with autosomal recessive inherited retinal dystrophy (PMID: 20647261, 29925512; Invitae). ClinVar contains an entry for this variant (Variation ID: 377403). 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%. 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

Last Updated: Sep 29, 2024

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