VCV000635493.6 - ClinVar

NM_000350.3(ABCA4):c.4696C>T (p.Leu1566Phe)

Germline

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.

(3)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Uncertain significance

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000350.3(ABCA4):c.4696C>T (p.Leu1566Phe)

Variation ID: 635493 Accession: VCV000635493.6

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94021923 (GRCh38) [ NCBI UCSC ] 1: 94487479 (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	Jul 15, 2019	Nov 17, 2024	Sep 18, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.4696C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Leu1566Phe	missense
NM_001425324.1:c.4474C>T	NP_001412253.1:p.Leu1492Phe	missense
NC_000001.11:g.94021923G>A
NC_000001.10:g.94487479G>A
NG_009073.1:g.104227C>T
NG_009073.2:g.104225C>T
NG_082117.1:g.1278G>A

... more HGVS ... less HGVS

Protein change

L1566F, L1492F

Other names

Canonical SPDI

NC_000001.11:94021922:G:A

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.

Trans-Omics for Precision Medicine (TOPMed) 0.00001

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Links

dbSNP: rs377398404 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	3759	4113
LOC126805793	-	-	-	GRCh38	-	215

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.
Cone-rod dystrophy 3	Uncertain significance (1)	no assertion criteria provided	Oct 9, 2018	RCV000786954.2
not provided	Uncertain significance (1)	criteria provided, single submitter	Aug 17, 2023	RCV001869182.4
not specified	Uncertain significance (1)	criteria provided, single submitter	Sep 18, 2024	RCV004782547.1

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 (Aug 17, 2023)	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: SCV002183311.3 First in ClinVar: Mar 28, 2022 Last updated: Feb 20, 2024	Publications: PubMed (1) PubMed: 30060493 Comment: This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1566 of the ABCA4 protein (p.Leu1566Phe). … (more) This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1566 of the ABCA4 protein (p.Leu1566Phe). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 635493). This missense change has been observed in individual(s) with Stargardt disease (PMID: 30060493). This variant is present in population databases (rs377398404, gnomAD 0.0009%). (less)
Uncertain significance (Sep 18, 2024)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV005395430.1 First in ClinVar: Nov 17, 2024 Last updated: Nov 17, 2024	Publications: PubMed (2) PubMed: 32307445‚ 30060493 Comment: Variant summary: ABCA4 c.4696C>T (p.Leu1566Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging … (more) Variant summary: ABCA4 c.4696C>T (p.Leu1566Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4696C>T has been reported in the literature in a complex genotype in at least 2 individuals affected with Stargardt disease (example, Nassisi_2018, Khan_2020), including 1 individual who carried a pathogenic variant on the same allele in cis. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32307445, 30060493). ClinVar contains an entry for this variant (Variation ID: 635493). Based on the evidence outlined above, the variant was classified as uncertain significance. (less)
Uncertain significance (Oct 09, 2018)	no assertion criteria provided Method: clinical testing	Cone-rod dystrophy 3 Affected status: yes Allele origin: germline	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare Accession: SCV000925859.1 First in ClinVar: Jul 15, 2019 Last updated: Jul 15, 2019

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 1566 of the ABCA4 protein (p.Leu1566Phe). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. 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: 635493). This missense change has been observed in individual(s) with Stargardt disease (PMID: 30060493). This variant is present in population databases (rs377398404, gnomAD 0.0009%).

Comment:

Variant summary: ABCA4 c.4696C>T (p.Leu1566Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251444 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4696C>T has been reported in the literature in a complex genotype in at least 2 individuals affected with Stargardt disease (example, Nassisi_2018, Khan_2020), including 1 individual who carried a pathogenic variant on the same allele in cis. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 32307445, 30060493). ClinVar contains an entry for this variant (Variation ID: 635493). Based on the evidence outlined above, the variant was classified as uncertain significance.

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
Resolving the dark matter of ABCA4 for 1054 Stargardt disease probands through integrated genomics and transcriptomics.	Khan M	Genetics in medicine : official journal of the American College of Medical Genetics	2020	PMID: 32307445
Expanding the Mutation Spectrum in ABCA4: Sixty Novel Disease Causing Variants and Their Associated Phenotype in a Large French Stargardt Cohort.	Nassisi M	International journal of molecular sciences	2018	PMID: 30060493

Text-mined citations for rs377398404 ...

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 Nov 19, 2024

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.4696C>T (p.Leu1566Phe)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs377398404 ...