ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.215T>C (p.Ile72Thr)

gnomAD frequency: 0.00001  dbSNP: rs781264043
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169295 SCV000220614 likely pathogenic Infantile hypophosphatasia 2014-08-21 criteria provided, single submitter literature only
Labcorp Genetics (formerly Invitae), Labcorp RCV001204937 SCV001376168 pathogenic not provided 2023-06-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388). 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. ClinVar contains an entry for this variant (Variation ID: 188928). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 19500388, 22397652; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs781264043, gnomAD 0.0009%). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 72 of the ALPL protein (p.Ile72Thr).
Baylor Genetics RCV003474904 SCV004193864 likely pathogenic Adult hypophosphatasia 2022-02-14 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005008090 SCV005640544 likely pathogenic Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia 2024-03-21 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV004552944 SCV004765176 pathogenic ALPL-related disorder 2023-12-18 no assertion criteria provided clinical testing The ALPL c.215T>C variant is predicted to result in the amino acid substitution p.Ile72Thr. This variant in the heterozygous state was reported in one patient affected with odontohypophosphatasia (Fauvert et al. 2009. PubMed ID: 19500388), and in the compound heterozygous state, this variant was found in a patient affected with perinatal hypophosphatasia (Whyte et al. 2012. PubMed ID: 22397652). In addition, a different variant affecting the same amino acid (p.Ile72Val) was reported in one individual with hypophosphatasia (Glotov et al. 2022. PubMed ID: 36361766). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-21887623-T-C). At PreventionGenetics, we have observed this variant in several unrelated individuals tested for ALPL (internal data). In summary, this variant is interpreted as pathogenic.

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