NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro) AND not provided

Germline classification:: Pathogenic (8 submissions)
Last evaluated:: Jan 30, 2025
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:: RCV000085410.57

Allele description [Variation Report for NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro)]

NM_000350.3(ABCA4):c.1622T>C (p.Leu541Pro)

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.1622T>C (p.Leu541Pro)

HGVS:

NC_000001.11:g.94063250A>G
NG_009073.1:g.62900T>C
NG_009073.2:g.62898T>C
NM_000350.3:c.1622T>CMANE SELECT
NM_001425324.1:c.1622T>C
NP_000341.2:p.Leu541Pro
NP_001412253.1:p.Leu541Pro
NC_000001.10:g.94528806A>G
NM_000350.2:c.1622T>C
P78363:p.Leu541Pro

Protein change:

L541P; LEU541PRO

Links:

UniProtKB: P78363#VAR_008415; OMIM: 601691.0023; dbSNP: rs61751392

NCBI 1000 Genomes Browser:

rs61751392

Molecular consequence:

NM_000350.3:c.1622T>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001425324.1:c.1622T>C - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided; RECLASSIFIED - ADRA2C POLYMORPHISM; RECLASSIFIED - ADRB1 POLYMORPHISM
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000117547	Retina International	no classification provided	not provided	unknown	not provided
SCV000577606	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Dec 9, 2024)	germline	clinical testing	Citation Link,
SCV000692637	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Mar 1, 2024)	germline	clinical testing	Citation Link,
SCV001234647	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 30, 2025)	germline	clinical testing	PubMed (12) [See all records that cite these PMIDs] 10206579, 11527935, 16103129, 19217903, 23755871, 24509150, 26593885, 28041643, 11017087, 25712131, 29847635, 28492532
SCV001447239	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Oct 23, 2020)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002020364	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 22, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005199084	Clinical Genetics Laboratory, Skane University Hospital Lund	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 13, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	22	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	7	not provided	not provided	not provided	not provided	clinical testing
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only

Citations

PubMed

A comprehensive survey of sequence variation in the ABCA4 (ABCR) gene in Stargardt disease and age-related macular degeneration.

Rivera A, White K, Stöhr H, Steiner K, Hemmrich N, Grimm T, Jurklies B, Lorenz B, Scholl HP, Apfelstedt-Sylla E, Weber BH.

Am J Hum Genet. 2000 Oct;67(4):800-13. Epub 2000 Aug 24.

PubMed [citation]

PMID:: 10958763
PMCID:: PMC1287885

Variation of clinical expression in patients with Stargardt dystrophy and sequence variations in the ABCR gene.

Fishman GA, Stone EM, Grover S, Derlacki DJ, Haines HL, Hockey RR.

Arch Ophthalmol. 1999 Apr;117(4):504-10.

PubMed [citation]

PMID:: 10206579

See all PubMed Citations (14)

Details of each submission

From Retina International, SCV000117547.1

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

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

From Eurofins Ntd Llc (ga), SCV000225507.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	7	not provided	not provided	clinical testing	PubMed (2)

#	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		7	not provided	not provided	not provided

From GeneDx, SCV000577606.9

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

Description

Functional studies demonstrate that the p.(L541P)/p.(A1038V) complex allele as well as the p.(L541P) and p.(A1038V) variants independently result in reduced ATPase activity; however, the affect of p.(A1038V) is milder compared to that of p.(L541P) alone or the p.(L541P)/p.(A1038V) complex allele (PMID: 11017087, 16103129, 25712131); 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: 37510321, 37498587, 35120629, 35260635, 31964843, 36460718, 32307445, 36672815, 29701254, 33749171, 34321860, 34906470, 9781034, 28118664, 29847635, 38003421, 37734845, 31429209, 32531858, 19217903, 19074458, 24713488, 24509150, 25712131, 10958761, 11328725, 26593885, 28041643, 16103129, 29555955, 29186038, 29068140, 30204727, 29925512, 30718709, 30653986, 32581362, 31573552, 33851411, 32619608, 32783370, 32037395, 32141364, 30643219, 33369172, 29114839, 28559085, 31456290, 35836572, 35119454, 34315337, 11017087, 11527935, 10958763, 22312191, 23918662)

#	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 CeGaT Center for Human Genetics Tuebingen, SCV000692637.31

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	22	not provided	not provided	clinical testing	not provided

Description

ABCA4: PM3:Very Strong, PM1, PM2, PP3, PS3:Supporting

#	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		22	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001234647.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (12)

Description

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 541 of the ABCA4 protein (p.Leu541Pro). This variant is present in population databases (rs61751392, gnomAD 0.07%). This missense change has been observed in individuals with Stargardt disease, cone-rod dystrophy, or retinitis pigmentosa (PMID: 10206579, 11527935, 16103129, 19217903, 23755871, 24509150, 26593885, 28041643). ClinVar contains an entry for this variant (Variation ID: 99067). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ABCA4 protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ABCA4 function (PMID: 11017087, 25712131, 29847635). 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 Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447239.1

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

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

From Revvity Omics, Revvity, SCV002020364.3

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

#	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 Clinical Genetics Laboratory, Skane University Hospital Lund, SCV005199084.1

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

#	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

Flagged submissions

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000225507	Eurofins Ntd Llc (ga)	flagged submission Reason: Claim with insufficient supporting evidence Notes: None (EGL Classification Definitions 2015)	Uncertain significance (Nov 16, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 10958763, 25712131 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000225507

Eurofins Ntd Llc (ga)

flagged submission

Reason: Claim with insufficient supporting evidence

Notes: None

(EGL Classification Definitions 2015)

Uncertain significance
(Nov 16, 2016)

germline

clinical testing

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

Citation Link

Last Updated: Feb 25, 2025

Relating variation to medicine