ClinVar Miner

Submissions for variant NM_030665.4(RAI1):c.4615C>T (p.Arg1539Cys)

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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 RCV002988649 SCV003291835 uncertain significance not provided 2025-01-14 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1539 of the RAI1 protein (p.Arg1539Cys). This variant is present in population databases (rs747006500, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAI1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2078462). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt RAI1 protein function with a positive predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
PreventionGenetics, part of Exact Sciences RCV004744521 SCV005345446 uncertain significance RAI1-related disorder 2024-04-08 no assertion criteria provided clinical testing The RAI1 c.4615C>T variant is predicted to result in the amino acid substitution p.Arg1539Cys. This variant was reported in an individual with Smith-Magenis syndrome, although detailed clinical information was not provided (Table 1, Figure S3, Brewer et al. 2020. PubMed ID: 32092540). This variant is reported in 0.022% of alleles in individuals of East Asian descent in gnomAD, which is higher than expected for a fully penetrant pathogenic variant in this gene. Although we suspect that this variant may be benign, 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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