ClinVar Miner

Submissions for variant NM_012281.3(KCND2):c.1207C>G (p.Pro403Ala)

dbSNP: rs1792826036
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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 RCV001302928 SCV001492155 pathogenic Early myoclonic encephalopathy 2023-12-28 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 403 of the KCND2 protein (p.Pro403Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of KCND2-related conditions (PMID: 34245260). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 1005965). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KCND2 protein function. Experimental studies have shown that this missense change affects KCND2 function (PMID: 19171772, 34245260). This variant disrupts the p.Pro403 amino acid residue in KCND2. Other variant(s) that disrupt this residue have been determined to be pathogenic (Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017817 SCV004848387 likely pathogenic Neurodevelopmental disorder 2022-01-14 criteria provided, single submitter clinical testing The p.Pro403Ala variant in KCND2 has been reported in 2 individuals with global developmental delay, vision impairment, and hypotonia, including one confirmed de novo occurrence (Zhang 2021 PMID: 34245260, Broad Institute Rare Genomes Project). This variant was absent from large population studies and has been reported in ClinVar (Variation ID 1005965). Computational prediction tools and conservation analyses suggest that this variant may impact the protein. In vitro functional studies also provide some evidence that it impacts protein function (Zhang 2021 PMID: 34245260). Finally, different changes at this position (p.Pro403Arg) and an adjacent position (p.Val404Leu, p.Val404Met) have occurred de novo individuals with overlapping phenotypes, indicating that changes to this region are not tolerated (Monies 2019 PMID: 31130284, Zhang 2021 PMID: 34245260). In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal dominant KCND2-related neurodevelopmental disorder. ACMG/AMP Criteria applied: PM2_Supporting, PP3, PS3_Supporting, PS4_Supporting, PS2_Moderate.

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