ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.1340T>C (p.Val447Ala)

dbSNP: rs1570309482
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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 RCV001971352 SCV002260865 likely pathogenic not provided 2021-03-16 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 447 of the ALPL protein (p.Val447Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of hypophosphatasia (Invitae). 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 ALPL protein function. 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.
Ambry Genetics RCV002573463 SCV003547018 uncertain significance Inborn genetic diseases 2020-11-10 criteria provided, single submitter clinical testing The c.1340T>C (p.V447A) alteration is located in exon 12 (coding exon 11) of the ALPL gene. This alteration results from a T to C substitution at nucleotide position 1340, causing the valine (V) at amino acid position 447 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the ALPL c.1340T>C alteration was not observed, with coverage at this position. The p.V447 amino acid is conserved in available vertebrate species. The in silico prediction for the p.V447A alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

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