Submissions for variant NM_000478.6(ALPL):c.667C>T (p.Arg223Trp)

gnomAD frequency: 0.00002  dbSNP: rs766076920

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000169383	SCV000220773	likely pathogenic	Infantile hypophosphatasia	2014-10-09	criteria provided, single submitter	literature only
Labcorp Genetics (formerly Invitae), Labcorp	RCV001208323	SCV001379703	pathogenic	not provided	2024-12-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 223 of the ALPL protein (p.Arg223Trp). This variant is present in population databases (rs766076920, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11760847, 23454488, 24100244). This variant is also known as p.Arg206Trp. ClinVar contains an entry for this variant (Variation ID: 189001). 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: 11760847, 23454488). This variant disrupts the p.Arg223 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11855933, 15694177, 23509830, 24100244). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DASA	RCV001831990	SCV002107089	pathogenic	Hypophosphatasia	2022-03-05	criteria provided, single submitter	clinical testing	Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23454488) - PS3_moderate.The c.667C>T;p.(Arg223Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 189001; PMID: 24100244; PMID: 23454488; PMID: 20383509) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Alk-phosphatase) - PM1. The variant is present at low allele frequencies population databases (rs766076920 – gnomAD 0.0001061%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg223Trp) was detected in trans with a pathogenic variant (PMID: 24100244; PMID: 23454488; PMID: 20383509) - PM3. Pathogenic missense variant in this residue have been reported (ClinVar ID: 381586) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was identified in an individual with a highly specific phenotype for the condition -PP4. In summary, the currently available evidence indicates that the variant is pathogenic.
Baylor Genetics	RCV003468842	SCV004193283	pathogenic	Adult hypophosphatasia	2024-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001831990	SCV004241599	pathogenic	Hypophosphatasia	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.667C>T (p.Arg223Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251478 control chromosomes (gnomAD). c.667C>T (also known as R206W) has been reported in the literature in multiple bi-allelic individuals affected with Hypophosphatasia (example: Mornet_1998, Brun-Heath_2005, Collman_2009, Orimo_2009, Hofmann_2013, McKiernan_2017, DelAngel_2020), however some of these individual had variants classified as VUS or likely benign in trans (Orimo_2009, Brun-Heath_2005). Multiple publications have reported experimental evidence evaluating an impact on protein function. All of these studies have shown variant effect results in <10% of normal activity (example: Hofmann_2013, Orimo_2009, Brun-Heath_2005). The following publications have been ascertained in the context of this evaluation (PMID: 23454488, 11760847, 18769927, 9781036, 28401263, 15694177, 32160374). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc.	RCV001831990	SCV002094067	pathogenic	Hypophosphatasia	2021-05-18	no assertion criteria provided	clinical testing