ClinVar Miner

Submissions for variant NM_001171.6(ABCC6):c.4279G>A (p.Glu1427Lys)

gnomAD frequency: 0.00001  dbSNP: rs756910757
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV003064324 SCV003443506 pathogenic not provided 2024-07-22 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1427 of the ABCC6 protein (p.Glu1427Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of pseudoxanthoma elasticum (PMID: 19284998, 28186352, 34906475; Invitae). ClinVar contains an entry for this variant (Variation ID: 2137788). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCC6 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
PreventionGenetics, part of Exact Sciences RCV004529199 SCV004109836 uncertain significance ABCC6-related disorder 2023-06-23 criteria provided, single submitter clinical testing The ABCC6 c.4279G>A variant is predicted to result in the amino acid substitution p.Glu1427Lys. This variant was reported in a patient with Angioid streaks (Sato et al 2009. PubMed ID: 19284998), a patient with pseudoxanthoma elasticum ( Iwanaga A et al 2017. PubMed ID: 28186352) and patients with Ectopic mineralization (Saeidian AH et al 2021. PubMed ID: 34906475). This variant is reported in 0.0055% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/16-16244559-C-T). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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