ClinVar Miner

Submissions for variant NM_006180.6(NTRK2):c.1304C>G (p.Ala435Gly)

gnomAD frequency: 0.00001  dbSNP: rs372937529
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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 RCV001891856 SCV002137709 uncertain significance not provided 2024-10-15 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 435 of the NTRK2 protein (p.Ala435Gly). This variant is present in population databases (rs372937529, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with NTRK2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1378899). 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 not expected to disrupt NTRK2 protein function with a negative 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 RCV004746478 SCV005354438 uncertain significance NTRK2-related disorder 2024-06-10 no assertion criteria provided clinical testing The NTRK2 c.1304C>G variant is predicted to result in the amino acid substitution p.Ala435Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0018% of alleles in individuals of European (Non-Finnish) descent in gnomAD v2 (as displayed in the table above). However, in gnomAD v4 (available only on GRCh38), this variant is reported in 19 alleles globally, which is likely too common for a highly penetrant pathogenic variant. Although we suspect that this variant may be benign, the clinical significance of this variant is classified as uncertain at this time due to insufficient functional and genetic evidence.

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