Submissions for variant NM_000478.6(ALPL):c.814C>T (p.Arg272Cys)

gnomAD frequency: 0.00001  dbSNP: rs121918020

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000817506	SCV000958070	pathogenic	not provided	2023-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 272 of the ALPL protein (p.Arg272Cys). This variant is present in population databases (rs121918020, gnomAD 0.006%). This missense change has been observed in individuals with hypophosphatasia (PMID: 17253930, 18559907, 24276437, 24378058). It has also been observed to segregate with disease in related individuals. This variant is also known as R255C. ClinVar contains an entry for this variant (Variation ID: 13684). 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 with a positive predictive value of 95%. This variant disrupts the p.Arg272 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 12815606, 15694177, 17253930, 18559907, 24276437, 24378058), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804731	SCV002051229	pathogenic	Hypophosphatasia	2021-12-18	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.814C>T (p.Arg272Cys) results in a non-conservative amino acid change located in the calcium site domain (Angel_2020) of 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 1.6e-05 in 251360 control chromosomes. c.814C>T has been reported in the literature as a compound heterozygous genotype in individuals affected with Hypophosphatasia (example, del Angel_2020, Spentchian_2006, Taketani_2014, Zhao_2013). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (del Angel_2020). The most pronounced variant effect results in <10% of normal tissue nonspecific alkaline phosphatase (TNSALP) activity in vitro. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV003473100	SCV004194919	pathogenic	Adult hypophosphatasia	2023-07-31	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549370	SCV004746842	pathogenic	ALPL-related disorder	2024-01-08	criteria provided, single submitter	clinical testing	The ALPL c.814C>T variant is predicted to result in the amino acid substitution p.Arg272Cys. This variant has been reported in several individuals with autosomal recessive hypophosphatasia (patient 1, Spentchian et al. 2006. PubMed ID: 17253930; Stevenson et al. 2008. PubMed ID: 18559907; Zhao et al. 2013. PubMed ID: 24378058; Zhang et al. 2021. PubMed ID: 33942288; Taketani et al. 2013. PubMed ID: 24276437). In vitro functional studies demonstrate that expression of this variant results in ~6% activity compared to wildtype (Table S1, Del Angel et al. 2020. PubMed ID: 32160374). This variant is reported in 0.0054% of alleles in individuals of East Asian descent in gnomAD. Additionally, different missense changes impacting the same amino acid (p.Arg272His and p.Arg272Leu) have been reported in individuals with hypophosphatasia (Brun-Heath et al. 2004. PubMed ID: 15694177; Spentchian et al. 2003. PubMed ID: 12815606). Taken together, the c.814C>T (p.Arg272Cys) variant is interpreted as pathogenic.
OMIM	RCV000014679	SCV000034934	pathogenic	Infantile hypophosphatasia	2008-09-01	no assertion criteria provided	literature only
OMIM	RCV000169779	SCV000034935	pathogenic	Childhood hypophosphatasia	2008-09-01	no assertion criteria provided	literature only
Natera, Inc.	RCV001804731	SCV002094076	pathogenic	Hypophosphatasia	2021-02-17	no assertion criteria provided	clinical testing