NM_000350.3(ABCA4):c.1844T>C (p.Val615Ala) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jun 23, 2023
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:: RCV001377317.13

Allele description [Variation Report for NM_000350.3(ABCA4):c.1844T>C (p.Val615Ala)]

NM_000350.3(ABCA4):c.1844T>C (p.Val615Ala)

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.1844T>C (p.Val615Ala)

HGVS:

NC_000001.11:g.94062670A>G
NG_009073.1:g.63480T>C
NG_009073.2:g.63478T>C
NM_000350.3:c.1844T>CMANE SELECT
NM_001425324.1:c.1844T>C
NP_000341.2:p.Val615Ala
NP_001412253.1:p.Val615Ala
NC_000001.10:g.94528226A>G
NM_000350.2:c.1844T>C

Protein change:

V615A

Links:

dbSNP: rs2101078285

NCBI 1000 Genomes Browser:

rs2101078285

Molecular consequence:

NM_000350.3:c.1844T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.1844T>C - 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
SCV001574623	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jun 23, 2023)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 29847651, 28492532
SCV001819897	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 19, 2021)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001574623

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jun 23, 2023)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

SCV001819897

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 19, 2021)

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

Mutations in GPR143/OA1 and ABCA4 Inform Interpretations of Short-Wavelength and Near-Infrared Fundus Autofluorescence.

Paavo M, Zhao J, Kim HJ, Lee W, Zernant J, Cai C, Allikmets R, Tsang SH, Sparrow JR.

Invest Ophthalmol Vis Sci. 2018 May 1;59(6):2459-2469. doi: 10.1167/iovs.18-24213.

PubMed [citation]

PMID:: 29847651
PMCID:: PMC5959512

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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001574623.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

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. 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. ClinVar contains an entry for this variant (Variation ID: 1066343). This missense change has been observed in individuals with Stargardt disease and clinical features of inherited retinal dystrophy (PMID: 29847651; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 615 of the ABCA4 protein (p.Val615Ala).

#	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, SCV001819897.3

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

Description

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed with a pathogenic variant in a patient with Stargardt disease in published literature, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Paavo et al., 2018); This variant is associated with the following publications: (PMID: 29847651)

#	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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