Submissions for variant NM_000478.6(ALPL):c.212G>A (p.Arg71His)

gnomAD frequency: 0.00001  dbSNP: rs121918003

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001382221	SCV001580892	pathogenic	not provided	2025-01-15	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 71 of the ALPL protein (p.Arg71His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with less severe presentations of hypophosphatasia and autosomal recessive infantile or childhood-onset hypophosphatasia (PMID: 11438998, 19500388, 22322541, 22397652, 25731960, 31760938). This variant is also known as p.Arg54His. ClinVar contains an entry for this variant (Variation ID: 1070177). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388). This variant disrupts the p.Arg71 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 1409720, 10839996, 11760847, 28127875), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001382221	SCV002013355	pathogenic	not provided	2024-09-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22322541, 11438998, 32160374, 22397652, 19500388, 32973344, 25731960, 12674323)
Baylor Genetics	RCV003388008	SCV004192961	pathogenic	Adult hypophosphatasia	2023-12-23	criteria provided, single submitter	clinical testing
Natera, Inc.	RCV001836391	SCV002094050	pathogenic	Hypophosphatasia	2019-04-18	no assertion criteria provided	clinical testing
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV003388008	SCV004099333	pathogenic	Adult hypophosphatasia	2023-10-30	no assertion criteria provided	clinical testing
Department of Pediatrics, Taizhou Central Hospital, Taizhou University Hospital	RCV004556085	SCV005045309	pathogenic	Infantile hypophosphatasia	2024-02-01	no assertion criteria provided	clinical testing