VCV000099028.11 - ClinVar

NM_000350.3(ABCA4):c.1037A>C (p.Lys346Thr)

Germline

Classification

criteria provided, conflicting classifications. Learn more about how ClinVar calculates review status.

Conflicting classifications of pathogenicity
Likely pathogenic(1); Uncertain significance(2)

3 out of 4 submissions contributed to this classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000350.3(ABCA4):c.1037A>C (p.Lys346Thr)

Variation ID: 99028 Accession: VCV000099028.11

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94080540 (GRCh38) [ NCBI UCSC ] 1: 94546096 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2014	May 31, 2025	Nov 26, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.1037A>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Lys346Thr	missense
NM_001425324.1:c.1037A>C	NP_001412253.1:p.Lys346Thr	missense
NC_000001.11:g.94080540T>G
NC_000001.10:g.94546096T>G
NG_009073.1:g.45610A>C
NG_009073.2:g.45608A>C

... more HGVS ... less HGVS

Protein change

K346T

Other names

Canonical SPDI

NC_000001.11:94080539:T:G

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00000

The Genome Aggregation Database (gnomAD), exomes 0.00001

Links

ClinGen: CA226864 dbSNP: rs61752389 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
ABCA4		-	-	GRCh38 GRCh37	4050	4431

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Conflicting classifications of pathogenicity (3)	criteria provided, conflicting classifications	Nov 26, 2024	RCV000085371.10
Retinal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Jul 26, 2019	RCV001073640.2

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Uncertain significance (Jul 26, 2019) C Contributing to aggregate classification	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001239191.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient

Likely pathogenic (Jul 01, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001540161.5 First in ClinVar: Mar 22, 2021 Last updated: Feb 25, 2025	Publications: PubMed (4) PubMed: 23953153‚ 26230768‚ 26551331‚ 35120629 Comment: This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 346 of the ABCA4 protein (p.Lys346Thr). … (more) This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 346 of the ABCA4 protein (p.Lys346Thr). This variant is present in population databases (rs61752389, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 23953153, 26230768, 26551331, 35120629). ClinVar contains an entry for this variant (Variation ID: 99028). 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%. 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. (less)

Uncertain significance (Nov 26, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV006081274.1 First in ClinVar: May 31, 2025 Last updated: May 31, 2025	Comment: Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; … (more) Not observed at significant frequency in large population cohorts (gnomAD); 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: 23953153, 35120629, 31964843, 31963381, 19324865, 20398653, 25139735, 21911583, 34874912) (less)

not provided (-) N Not contributing to aggregate classification	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: not provided	Retina International Accession: SCV000117508.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.1037A>C

Comment:

This sequence change replaces lysine, which is basic and polar, with threonine, which is neutral and polar, at codon 346 of the ABCA4 protein (p.Lys346Thr). This variant is present in population databases (rs61752389, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of ABCA4-related conditions (PMID: 23953153, 26230768, 26551331, 35120629). ClinVar contains an entry for this variant (Variation ID: 99028). 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%. 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.

Comment:

Not observed at significant frequency in large population cohorts (gnomAD); 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: 23953153, 35120629, 31964843, 31963381, 19324865, 20398653, 25139735, 21911583, 34874912)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Personalized genetic counseling for Stargardt disease: Offspring risk estimates based on variant severity.	Cornelis SS	American journal of human genetics	2022	PMID: 35120629
Quantitative Fundus Autofluorescence and Optical Coherence Tomography in ABCA4 Carriers.	Duncker T	Investigative ophthalmology & visual science	2015	PMID: 26551331
Flecks in Recessive Stargardt Disease: Short-Wavelength Autofluorescence, Near-Infrared Autofluorescence, and Optical Coherence Tomography.	Sparrow JR	Investigative ophthalmology & visual science	2015	PMID: 26230768
Clinical and molecular analysis of Stargardt disease with preserved foveal structure and function.	Fujinami K	American journal of ophthalmology	2013	PMID: 23953153

Text-mined citations for rs61752389 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jun 01, 2025

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.1037A>C (p.Lys346Thr)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs61752389 ...