Submissions for variant NM_000478.6(ALPL):c.668G>A (p.Arg223Gln)

gnomAD frequency: 0.00001  dbSNP: rs199665722

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000428517	SCV000521021	pathogenic	not provided	2024-11-11	criteria provided, single submitter	clinical testing	Previously reported (as R206Q or c.668G>A due to the use of alternative nomenclature) in association with autosomal recessive hypophosphatasia (PMID: 11855933, 20924064); Reported previously as a de novo variant in a patient with infantile hypophosphatasia who also harbored a second maternally inherited variant; variants were assumed to be compound heterozygous (PMID: 33827627); 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: 34662886, 15660230, 20924064, 31793067, 24100244, 15694177, 18925618, 24276437, 31754721, 30293248, 34673643, Jeon_2022_Abstract, 32160374, 37600704, 29236161, 11855933, 23509830, 33827627)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000428517	SCV001226648	pathogenic	not provided	2024-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 223 of the ALPL protein (p.Arg223Gln). This variant is present in population databases (rs199665722, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11855933, 15694177, 24100244). This variant is also known as p.Arg206Gln. ClinVar contains an entry for this variant (Variation ID: 381586). 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: 15694177, 23509830). For these reasons, this variant has been classified as Pathogenic.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000428517	SCV001473298	pathogenic	not provided	2020-03-03	criteria provided, single submitter	clinical testing	The ALPL variant c.668G>A; p.Arg223Gln (rs552831415), also known as R206Q, is reported in the literature in the compound heterozygous state in multiple individuals affected with hypophosphatasia (de Roo 204, Liu 2010, Michigami 2005, Mumm 2002, Simon-Bouy 2008, Taketani 2014). This variant is reported in ClinVar (Variation ID: 381586), and is only observed on four alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. The arginine at codon 223 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional analyses of the variant protein demonstrate a significant decrease in function (Zhu 2012). Based on available information, this variant is considered to be pathogenic. References: de Roo MGA et al. Infantile hypophosphatasia without bone deformities presenting with severe pyridoxine-resistant seizures. Mol Genet Metab. 2014 Mar;111(3):404-407. Liu H et al. Genetic etiology and dental pulp cell deficiency of hypophosphatasia. J Dent Res. 2010 Dec;89(12):1373-7. Michigami T et al. Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia. Eur J Pediatr. 2005 May;164(5):277-82. Mumm S et al. Denaturing gradient gel electrophoresis analysis of the tissue nonspecific alkaline phosphatase isoenzyme gene in hypophosphatasia. Mol Genet Metab. 2002 Feb;75(2):143-53. Simon-Bouy B et al. Hypophosphatasia: molecular testing of 19 prenatal cases and discussion about genetic counseling. Prenat Diagn. 2008 Nov;28(11):993-8. Taketani T et al. Clinical and genetic aspects of hypophosphatasia in Japanese patients. Arch Dis Child. 2014 Mar;99(3):211-5. Zhu T et al. Functional evaluation of mutations in the tissue-nonspecific alkaline phosphatase gene. Chin J Dent Res. 2012;15(2):99-104.
Fulgent Genetics, Fulgent Genetics	RCV002480299	SCV002776087	pathogenic	Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia	2024-04-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003470381	SCV004193161	pathogenic	Adult hypophosphatasia	2024-03-05	criteria provided, single submitter	clinical testing
Counsyl	RCV000984145	SCV001132121	likely pathogenic	Infantile hypophosphatasia	2018-11-01	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001833531	SCV002094068	pathogenic	Hypophosphatasia	2020-06-03	no assertion criteria provided	clinical testing