VCV000298232.17 - ClinVar

NM_000350.3(ABCA4):c.4925G>T (p.Ser1642Ile)

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.

(8)

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.

Conflicting classifications of pathogenicity
Uncertain significance(2); Benign(1); Likely benign(5)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000350.3(ABCA4):c.4925G>T (p.Ser1642Ile)

Variation ID: 298232 Accession: VCV000298232.17

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 1p22.1 1: 94021333 (GRCh38) [ NCBI UCSC ] 1: 94486889 (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	Dec 6, 2016	Feb 14, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000350.3:c.4925G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_000341.2:p.Ser1642Ile	missense
NM_001425324.1:c.4703G>T	NP_001412253.1:p.Ser1568Ile	missense
NC_000001.11:g.94021333C>A
NC_000001.10:g.94486889C>A
NG_009073.1:g.104817G>T
NG_009073.2:g.104815G>T
NG_082117.1:g.688C>A

... more HGVS ... less HGVS

Protein change

S1642I, S1568I

Other names

Canonical SPDI

NC_000001.11:94021332:C: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.

0.00339 (A)

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

The Genome Aggregation Database (gnomAD), exomes 0.00102

Exome Aggregation Consortium (ExAC) 0.00122

1000 Genomes Project 30x 0.00312

1000 Genomes Project 0.00339

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00415

The Genome Aggregation Database (gnomAD) 0.00425

Trans-Omics for Precision Medicine (TOPMed) 0.00453

Links

ClinGen: CA957429 dbSNP: rs114518437 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	-	-
LOC126805793	-	-	-	GRCh38	-	-

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, Recessive	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000301076.5
Retinitis Pigmentosa, Recessive	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000340669.5
Macular degeneration	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000353628.5
Stargardt Disease, Recessive	Likely benign (1)	criteria provided, single submitter	Jun 14, 2016	RCV000393458.5
not provided	Conflicting interpretations of pathogenicity (2)	criteria provided, conflicting classifications	Jan 31, 2024	RCV000486564.12
ABCA4-related disorder	Likely benign (1)	criteria provided, single submitter	Apr 28, 2017	RCV001101750.4
Retinal dystrophy	Uncertain significance (1)	criteria provided, single submitter	Feb 25, 2019	RCV001075649.2

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.
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Macular Degeneration Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359291.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Stargardt Disease, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359289.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Retinitis Pigmentosa, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359288.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Likely benign (Jun 14, 2016)	criteria provided, single submitter (ICSL Variant Classification 20161018) Method: clinical testing	Cone-Rod Dystrophy, Recessive Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV000359290.2 First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016
Uncertain significance (Dec 20, 2018)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000564536.3 First in ClinVar: Apr 29, 2017 Last updated: Apr 29, 2017	Comment: The S1642I variant in the ABCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The … (more) The S1642I variant in the ABCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S1642I variant is observed in 348/24,036 (1.4%) alleles from individuals of African background and 372/277,170 (0.13%) total alleles in large population cohorts, including one homozygous individual, which is greater than expected for this disorder (Lek et al., 2016). However, the S1642I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S1642I as a variant of uncertain significance. (less)
Uncertain significance (Feb 25, 2019)	criteria provided, single submitter (Blueprint Genetics Variant Classification Scheme) Method: clinical testing	Retinal dystrophy Affected status: yes Allele origin: germline	Blueprint Genetics Accession: SCV001241276.1 First in ClinVar: Apr 18, 2020 Last updated: Apr 18, 2020 Comment: My Retina Tracker patient
Likely benign (Apr 28, 2017)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	ABCA4-Related Disorders Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001258387.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more) This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
Benign (Jan 31, 2024)	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: SCV001039157.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024

Comment:

The S1642I variant in the ABCA4 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The S1642I variant is observed in 348/24,036 (1.4%) alleles from individuals of African background and 372/277,170 (0.13%) total alleles in large population cohorts, including one homozygous individual, which is greater than expected for this disorder (Lek et al., 2016). However, the S1642I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret S1642I as a variant of uncertain significance.

Comment:

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.

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

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs114518437 ...

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 Sep 29, 2024

ClinVar Genomic variation as it relates to human health

NM_000350.3(ABCA4):c.4925G>T (p.Ser1642Ile)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs114518437 ...