NM_000350.3(ABCA4):c.4462T>C (p.Cys1488Arg) AND not provided

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Sep 15, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
5 submissions [Details]
Record status:
current
Accession:
RCV000085637.8

Allele description [Variation Report for NM_000350.3(ABCA4):c.4462T>C (p.Cys1488Arg)]

NM_000350.3(ABCA4):c.4462T>C (p.Cys1488Arg)

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.4462T>C (p.Cys1488Arg)
HGVS:
  • NC_000001.11:g.94029522A>G
  • NG_009073.1:g.96628T>C
  • NM_000350.3:c.4462T>CMANE SELECT
  • NP_000341.2:p.Cys1488Arg
  • NC_000001.10:g.94495078A>G
  • NM_000350.2:c.4462T>C
  • P78363:p.Cys1488Arg
Protein change:
C1488R
Links:
UniProtKB: P78363#VAR_008453; dbSNP: rs61750146
NCBI 1000 Genomes Browser:
rs61750146
Molecular consequence:
  • NM_000350.3:c.4462T>C - missense variant - [Sequence Ontology: SO:0001583]
Observations:
2

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000117776Retina Internationalno assertion providednot providednot providednot provided

SCV000321351GeneDxcriteria provided, single submitter
Pathogenic
(Oct 12, 2016)
germlineclinical testing

Citation Link,

SCV001222273Invitaecriteria provided, single submitter
Pathogenic
(Dec 14, 2019)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001248244CeGaT Praxis fuer Humangenetik Tuebingencriteria provided, single submitter
Pathogenic
(Jun 1, 2018)
germlineclinical testing

Citation Link,

SCV001905554Institute of Medical Genetics and Applied Genomics, University Hospital Tübingencriteria provided, single submitter
Likely pathogenic
(Sep 15, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

Description

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyes2not providednot provided1not providedclinical testing
not providednot providednot providednot providednot providednot provided1not providedliterature only
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.

Birtel J, Eisenberger T, Gliem M, Müller PL, Herrmann P, Betz C, Zahnleiter D, Neuhaus C, Lenzner S, Holz FG, Mangold E, Bolz HJ, Charbel Issa P.

Sci Rep. 2018 Mar 19;8(1):4824. doi: 10.1038/s41598-018-22096-0.

PubMed [citation]
PMID:
29555955
PMCID:
PMC5859282

Clinically Focused Molecular Investigation of 1000 Consecutive Families with Inherited Retinal Disease.

Stone EM, Andorf JL, Whitmore SS, DeLuca AP, Giacalone JC, Streb LM, Braun TA, Mullins RF, Scheetz TE, Sheffield VC, Tucker BA.

Ophthalmology. 2017 Sep;124(9):1314-1331. doi: 10.1016/j.ophtha.2017.04.008. Epub 2017 May 27.

PubMed [citation]
PMID:
28559085
PMCID:
PMC5565704
See all PubMed Citations (7)

Details of each submission

From Retina International, SCV000117776.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providednot providednot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1not providednot provided1not providednot providednot providednot providednot providednot provided

From GeneDx, SCV000321351.7

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The C1488R pathogenic variant in the ABCA4 gene has been published previously in association with Stargardt disease (Lewis et al., 1999; Briggs et al., 2001; Webster et al., 2001). The variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. C1488R 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. This substitution occurs at a position that is conserved across species. Functional studies have shown that C1488R results in lowered ATPase activity compared to wild type (Sun et al., 2000). Missense variants in the same codon (C1488Y/F) and in nearby residues (P1486L, C1490Y) have been reported in the Human Gene Mutation Database in association with Stargardt disease (Stenson et al., 2014), supporting the functional importance of this region of the protein.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Invitae, SCV001222273.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces cysteine with arginine at codon 1488 of the ABCA4 protein (p.Cys1488Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is present in population databases (rs61750146, ExAC 0.003%). This variant has been observed in individual(s) with ABCA4-related conditions (PMID: 29555955, 28559085, 29925512, 22449572). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 99284). This variant has been reported to affect ABCA4 protein function (PMID: 11017087). For these reasons, this variant has been classified as Pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From CeGaT Praxis fuer Humangenetik Tuebingen, SCV001248244.6

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot provided2not providednot providednot provided

From Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen, SCV001905554.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyes1not providednot providednot providednot providednot providednot provided

Last Updated: Nov 27, 2021

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