ClinVar Miner

Submissions for variant NM_000520.6(HEXA):c.32T>C (p.Leu11Pro)

gnomAD frequency: 0.00001  dbSNP: rs141120074
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV001002232 SCV001160107 uncertain significance not specified 2018-11-15 criteria provided, single submitter clinical testing The HEXA c.32T>C; p.Leu11Pro variant (rs141120074), to our knowledge, is not reported in the medical literature or gene specific databases. This variant is found on only three chromosomes in the Genome Aggregation Database, indicating it is not a common polymorphism. The leucine at codon 11 is highly conserved, it occurs within a hydrophobic signal peptide sequence (Myerowitz 1997), and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. However, due to limited information, the clinical significance of the p.Leu11Pro variant is uncertain at this time. References: Myerowitz R. Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A gene. Hum Mutat. 1997;9(3):195-208.
Labcorp Genetics (formerly Invitae), Labcorp RCV001827157 SCV002945160 pathogenic Tay-Sachs disease 2024-01-27 criteria provided, single submitter clinical testing This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 11 of the HEXA protein (p.Leu11Pro). This variant is present in population databases (rs141120074, gnomAD 0.006%). This missense change has been observed in individual(s) with clinical features of Tay-Sachs disease (PMID: 31242539; Invitae). ClinVar contains an entry for this variant (Variation ID: 811826). 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 HEXA protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Natera, Inc. RCV001827157 SCV002089766 uncertain significance Tay-Sachs disease 2018-09-04 no assertion criteria provided clinical testing

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