ClinVar Miner

Submissions for variant NM_000521.4(HEXB):c.1630C>A (p.Gln544Lys)

dbSNP: rs766477016
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482174 SCV000573016 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the HEXB gene. The Q544K variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The Q544K variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Q544K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Labcorp Genetics (formerly Invitae), Labcorp RCV002525932 SCV003261581 uncertain significance Sandhoff disease 2022-05-04 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 544 of the HEXB protein (p.Gln544Lys). This variant is present in population databases (rs766477016, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with HEXB-related conditions. ClinVar contains an entry for this variant (Variation ID: 423332). 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 not expected to disrupt HEXB protein function. 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.

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