NM_000350.3(ABCA4):c.122G>A (p.Trp41Ter) AND not provided

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jun 12, 2022
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:: RCV000085379.8

Allele description [Variation Report for NM_000350.3(ABCA4):c.122G>A (p.Trp41Ter)]

NM_000350.3(ABCA4):c.122G>A (p.Trp41Ter)

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.122G>A (p.Trp41Ter)

HGVS:

NC_000001.11:g.94113011C>T
NG_009073.1:g.13139G>A
NG_009073.2:g.13137G>A
NM_000350.3:c.122G>AMANE SELECT
NM_001425324.1:c.122G>A
NP_000341.2:p.Trp41Ter
NP_001412253.1:p.Trp41Ter
NC_000001.10:g.94578567C>T
NM_000350.2:c.122G>A

Protein change:

W41*

Links:

dbSNP: rs61751410

NCBI 1000 Genomes Browser:

rs61751410

Molecular consequence:

NM_000350.3:c.122G>A - nonsense - [Sequence Ontology: SO:0001587]
NM_001425324.1:c.122G>A - nonsense - [Sequence Ontology: SO:0001587]

Functional consequence:

sequence_variant_affecting_splicing [Sequence Ontology: SO:1000071]

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
SCV000117516	Retina International	no classification provided	not provided	not provided	not provided
SCV000890154	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Aug 7, 2018)	germline	clinical testing	Citation Link,
SCV001222994	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jun 12, 2022)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 19074458, 25444351, 30670881, 10958761, 24938718, 25312043, 26780318, 28492532
SCV001480161	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 1, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Description

http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.122G>A: SCV000117516

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not provided	not provided	not provided	not provided	not provided	1	not provided	literature only
not provided	germline	yes	not provided	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

ABCA4 disease progression and a proposed strategy for gene therapy.

Cideciyan AV, Swider M, Aleman TS, Tsybovsky Y, Schwartz SB, Windsor EA, Roman AJ, Sumaroka A, Steinberg JD, Jacobson SG, Stone EM, Palczewski K.

Hum Mol Genet. 2009 Mar 1;18(5):931-41. doi: 10.1093/hmg/ddn421. Epub 2008 Dec 12.

PubMed [citation]

PMID:: 19074458
PMCID:: PMC2640207

Early-onset stargardt disease: phenotypic and genotypic characteristics.

Lambertus S, van Huet RA, Bax NM, Hoefsloot LH, Cremers FP, Boon CJ, Klevering BJ, Hoyng CB.

Ophthalmology. 2015 Feb;122(2):335-44. doi: 10.1016/j.ophtha.2014.08.032. Epub 2014 Oct 17.

PubMed [citation]

PMID:: 25444351

See all PubMed Citations (9)

Details of each submission

From Retina International, SCV000117516.1

#	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	not provided	not provided	1	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV000890154.1

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

Description

The W41X nonsense variant has been reported previously in association with ABCA4-related disorders (Cideciyan et al., 2009; Schulz et al., 2017). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We consider this variant to be pathogenic.

#	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 Invitae, SCV001222994.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (8)

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. ClinVar contains an entry for this variant (Variation ID: 99036). This premature translational stop signal has been observed in individuals with ABCA4-related retinal dystrophy (PMID: 19074458, 25444351, 30670881). This variant is present in population databases (rs61751410, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Trp41*) 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

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001480161.1

#	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

Last Updated: Mar 30, 2024

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