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(ABCA4):c.5371dup (p.Ala1791fs)

CA2573335086

2585325 (ClinVar)

Gene: ABCA4 (HGNC:24)

Condition: ABCA4-related retinopathy (MONDO:0800406)

Inheritance Mode: Autosomal recessive inheritance

UUID: 5d7bb5c5-8f11-4c04-a160-187990cf16ea

Approved on: 2025-12-05

Published on: 2025-12-19

HGVS expressions

NM_000350.3:c.5371dup

NM_000350.3(ABCA4):c.5371dup (p.Ala1791fs)

NC_000001.11:g.94014632dup

CM000663.2:g.94014632dup

NC_000001.10:g.94480188dup

CM000663.1:g.94480188dup

NC_000001.9:g.94252776dup

NG_009073.1:g.111518dup

ENST00000370225.4:c.5371dup

ENST00000370225.3:c.5371dup

ENST00000536513.5:c.1747dup

NM_000350.2:c.5371dup

Pathogenic

PVS1 PM2_Supporting PM3_Supporting

PS4

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.5371dup (p.Ala1791GlyfsTer9) variant in ABCA4 is a frameshift variant predicted to cause a premature stop codon in biologically-relevant exon 38/50 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 one individual with ABCA4-related retinopathy. This individual was compound heterozygous for the variant and a pathogenic variant (c.5882G>A; p.Gly1961Glu) presumed to be in trans by NGS targeted gene panel testing (PM3_Supporting; PMID: 31816670). 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 (Specification Version 1): PVS1, PM3_Supporting, PM2_Supporting.

PVS1

This is a frameshift variant located in exon 38 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).

PM3_Supporting

Variant detected in proband with cone dystrophy who also harbors pathogenic variant ABCA4:c.5882G>A, p.G1961E. Testing involved NGS gene panel (200-7000 genes) associated with retinal phenotypes. Authors noted limitations on phase determination. Awarded 0.5 points towards criteria PM3_Supporting consideration.

PS4

While odds ratio for this variant is above 5, the confidence interval contains 1 (PMID:35120629). Therefore, PS4 is not met.

Curation History

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