NM_000350.3(ABCA4):c.3085C>T (p.Gln1029Ter) AND not provided

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Aug 22, 2023
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:: RCV000085546.5

Allele description [Variation Report for NM_000350.3(ABCA4):c.3085C>T (p.Gln1029Ter)]

NM_000350.3(ABCA4):c.3085C>T (p.Gln1029Ter)

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.3085C>T (p.Gln1029Ter)

HGVS:

NC_000001.11:g.94043441G>A
NG_009073.1:g.82709C>T
NG_009073.2:g.82707C>T
NM_000350.3:c.3085C>TMANE SELECT
NM_001425324.1:c.2863C>T
NP_000341.2:p.Gln1029Ter
NP_001412253.1:p.Gln955Ter
NC_000001.10:g.94508997G>A
NM_000350.2:c.3085C>T

Protein change:

Q1029*

Links:

dbSNP: rs61751397

NCBI 1000 Genomes Browser:

rs61751397

Molecular consequence:

NM_000350.3:c.3085C>T - nonsense - [Sequence Ontology: SO:0001587]
NM_001425324.1:c.2863C>T - nonsense - [Sequence Ontology: SO:0001587]

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
SCV000117683	Retina International	no classification provided	not provided	not provided	not provided
SCV000748178	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Pathogenic (Apr 9, 2018)	germline	clinical testing	Citation Link,
SCV002246989	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Aug 22, 2023)	germline	clinical testing	PubMed (8) [See all records that cite these PMIDs] 10958761, 24938718, 25312043, 26780318, 12037008, 28118664, 29555955, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000117683

Retina International

no classification provided

not provided

SCV000748178

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification (06012015))

Pathogenic
(Apr 9, 2018)

germline

clinical testing

Citation Link,

SCV002246989

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Aug 22, 2023)

germline

clinical testing

PubMed (8)
[See all records that cite these PMIDs]

Description

http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg19&id=RISN_ABCR:c.3085C>T: SCV000117683

Help

Summary from all submissions

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

Mutations in the ABCA4 (ABCR) gene are the major cause of autosomal recessive cone-rod dystrophy.

Maugeri A, Klevering BJ, Rohrschneider K, Blankenagel A, Brunner HG, Deutman AF, Hoyng CB, Cremers FP.

Am J Hum Genet. 2000 Oct;67(4):960-6. Epub 2000 Aug 24.

PubMed [citation]

PMID:: 10958761
PMCID:: PMC1287897

Mutations of 60 known causative genes in 157 families with retinitis pigmentosa based on exome sequencing.

Xu Y, Guan L, Shen T, Zhang J, Xiao X, Jiang H, Li S, Yang J, Jia X, Yin Y, Guo X, Wang J, Zhang Q.

Hum Genet. 2014 Oct;133(10):1255-71. doi: 10.1007/s00439-014-1460-2. Epub 2014 Jun 18.

PubMed [citation]

PMID:: 24938718

See all PubMed Citations (8)

Details of each submission

From Retina International, SCV000117683.1

#	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, SCV000748178.3

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

Description

The Q1029X variant in the ABCA4 gene has been reported previously in association with cone rod dystrophy, when seen in the heterozygous state with a second ABCA4 variant (Klevering et al., 2002; Thiadens et al., 2012). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Q1029X variant is not observed in large population cohorts (Lek et al., 2016). We interpret Q1029X as a pathogenic variant.

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV002246989.3

#	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. This sequence change creates a premature translational stop signal (p.Gln1029*) 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). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with cone-rod dystrophy and Stargardt disease (PMID: 12037008, 28118664, 29555955). ClinVar contains an entry for this variant (Variation ID: 99197). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site.

#	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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