Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Variant: NM_000350.3:c.3007C>T

CA341275107

Gene: ABCA4 (HGNC:24)

Condition: ABCA4-related retinopathy (MONDO:0800406)

Inheritance Mode: Autosomal recessive inheritance

UUID: 87f34277-cda0-439b-bfda-e569e012ef1e

Approved on: 2025-12-05

Published on: 2025-12-22

HGVS expressions

NM_000350.3:c.3007C>T

NC_000001.11:g.94044656G>A

CM000663.2:g.94044656G>A

NC_000001.10:g.94510212G>A

CM000663.1:g.94510212G>A

NC_000001.9:g.94282800G>A

NG_009073.1:g.81494C>T

ENST00000370225.4:c.3007C>T

ENST00000370225.3:c.3007C>T

ENST00000536513.5:c.-64-4567C>T

NM_000350.2:c.3007C>T

Pathogenic

PM3_Supporting PVS1 PM2_Supporting

PS4 PP4

Evidence Links 0

Expert Panel

ABCA4 VCEP

Criteria Specification Information

Criteria Specification: ClinGen ABCA4 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ABCA4 Version 1.0.0

Criteria Specification Approval History

Criteria Specifications for this VCEP

Evidence submitted by expert panel

ABCA4 VCEP

The NM_000350.3:c.3007C>T (p.Gln1003Ter) variant in ABCA4 is a nonsense variant predicted to cause a premature stop codon in biologically relevant exon 20/50 leading to nonsense mediated decay in a gene in which loss-of-function is an established disease mechanism (PVS1). This variant is absent from gnomAD v4.1.0 (PM2_Supporting). This variant has been detected in at least two individuals with ABCA4-related retinopathy, of which, at least one was compound heterozygous for the variant and a pathogenic variant (PM3_Supporting; PMID: 28446513, 33909047). In summary, this variant meets the criteria to be classified as Pathogenic for ABCA4-related retinopathy based on the ACMG/AMP criteria applied, as specified by the ClinGen ABCA4 VCEP (v1.0.0): PSV1, PM3_Supporting, PM2_Supporting.

PM3_Supporting

Patient 3792 (part of a large familial ABCA4 disease cohort) found to be compound heterozygous for c.3007C>T (p.Gln1003*) and pathogenic variant c.5882G>A (p.G1961E). Phase not confirmed. 0.5pts applied towards PM3_Supporting.

PVS1

This is a nonsense variant located in exon 20 out of 50, and introduces a premature stop codon between codons 1-2255 (PVS1).

PM2_Supporting

This variant is absent from gnomAD v4.1.0 (PM2_Supporting).

PS4

The OR is infinity and the CI is 0.31 to infinity, which is above the ABCA4 VCEP threshold of ≥5, but the CI contains 1 which does not meet the criterion for PS4 set by the ABCA4 VCEP (PS4_not met; PMID: 35120629).

PP4

Onset at age 6 years (+0.5pts), compound heterozygous for two variants in ABCA4 gene c.3007C>T and c.768G>T (+0.5pts), WES testing (+2 pts), bull's eye lesions (+1pt), decreased central visual acuity (+1pt). Inquiry to author regarding presence of macular flecks were not received in timely manner. Upon review of macular images, the ABCA4 VCEP determined the patient did not show macular flecks, thereby, PP4 is not met.

Curation History

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