ClinVar Miner

Submissions for variant NM_000187.4(HGD):c.473C>T (p.Pro158Leu)

gnomAD frequency: 0.00001  dbSNP: rs375396766
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000668985 SCV000793674 uncertain significance Alkaptonuria 2017-11-14 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000668985 SCV002793102 uncertain significance Alkaptonuria 2022-03-23 criteria provided, single submitter clinical testing
Invitae RCV000668985 SCV004293141 likely pathogenic Alkaptonuria 2023-12-03 criteria provided, single submitter clinical testing This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 158 of the HGD protein (p.Pro158Leu). This variant is present in population databases (rs375396766, gnomAD 0.01%). This missense change has been observed in individual(s) with HGD-related conditions (PMID: 19862842, 21822197). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 553516). 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 HGD protein function with a negative predictive value of 80%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences RCV000668985 SCV004098968 pathogenic Alkaptonuria no assertion criteria provided research The variant was originally described in AKU patient in PMID:19862842. It has been submitted to the HGD gene mutation database (http://hgddatabase.cvtisr.sk/, DB-ID: AKU_00048).

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