ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.1417G>A (p.Gly473Ser)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001048323 SCV001212322 likely pathogenic not provided 2019-12-29 criteria provided, single submitter clinical testing This sequence change replaces Glycine with Serine at codon 473 of the ALPL protein (p.Gly473Ser). The Glycine residue is highly conserved and there is a small physicochemical difference between Glycine and Serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Hypophosphatasia and segregated with disease in one family (PMID: 9781036, 28127875, 31077853). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: Deleterious; PolyPhen-2: Probably Damaging; Align-GVGD: Class C0). 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001286684 SCV001473296 likely pathogenic none provided 2020-03-03 criteria provided, single submitter clinical testing The ALPL c.1417G>A; p.Gly473Ser variant, also known as G456S, is reported in the literature in the compound heterozygous state in individuals affected with hypophosphatasia (Martins 2019, Mornet 1998). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glycine at codon 473 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. References: Martins L et al. A novel combination of biallelic ALPL mutations associated with adult hypophosphatasia: A phenotype-genotype association and computational analysis study. Bone. 2019 Aug;125:128-139. Mornet E et al. Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia. Eur J Hum Genet. 1998 Jul-Aug;6(4):308-14.

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