NM_000350.3(ABCA4):c.1988G>A (p.Trp663Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 29, 2021
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:: RCV000414150.31

Allele description [Variation Report for NM_000350.3(ABCA4):c.1988G>A (p.Trp663Ter)]

NM_000350.3(ABCA4):c.1988G>A (p.Trp663Ter)

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.1988G>A (p.Trp663Ter)

HGVS:

NC_000001.11:g.94060709C>T
NG_009073.1:g.65441G>A
NG_009073.2:g.65439G>A
NM_000350.3:c.1988G>AMANE SELECT
NM_001425324.1:c.1988G>A
NP_000341.2:p.Trp663Ter
NP_001412253.1:p.Trp663Ter
NC_000001.10:g.94526265C>T
NM_000350.2:c.1988G>A

Protein change:

W663*

Links:

dbSNP: rs865990202

NCBI 1000 Genomes Browser:

rs865990202

Molecular consequence:

NM_000350.3:c.1988G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001425324.1:c.1988G>A - nonsense - [Sequence Ontology: SO:0001587]

Observations:

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
SCV000490369	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Jul 19, 2016)	germline	clinical testing	Citation Link,
SCV001245783	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Apr 1, 2017)	germline	clinical testing	Citation Link,
SCV001447307	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]
SCV001590409	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 29, 2021)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 10958763, 28559085, 10958761, 24938718, 25312043, 26780318, 28492532

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	3	not provided	not provided	1	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

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

See all PubMed Citations (8)

Details of each submission

From GeneDx, SCV000490369.2

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

Description

The W663X pathogenic variant has been reported multiple times in individuals with Stargardt disease and retinal dystrophy (Rivera et al., 2000; Burke et al., 2012; Tiwari et al., 2016). The G1203E variant has been reported in association with autosomal recessive code-rod dystrophy, however specific clinical and segregation information was not provided (Kitiratschky et al., 2008; Zlotogora et al., 2010). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.

#	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, SCV001245783.26

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	3	not provided	not provided	clinical testing	not provided

#	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		3	not provided	not provided	not provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001447307.1

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001590409.4

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

Description

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This variant has been observed in individual(s) with Stargradt disease (PMID: 10958763, 28559085). ClinVar contains an entry for this variant (Variation ID: 372289). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp663*) in the ABCA4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCA4 are known to be pathogenic (PMID: 10958761, 24938718, 25312043, 26780318).

#	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

Last Updated: Nov 3, 2024

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