Submissions for variant NM_000478.6(ALPL):c.1001G>A (p.Gly334Asp)

dbSNP: rs121918009

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000224376	SCV000280657	pathogenic	not provided	2016-11-04	criteria provided, single submitter	clinical testing
Counsyl	RCV000014663	SCV000485319	likely pathogenic	Infantile hypophosphatasia	2015-11-23	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000763301	SCV000893966	pathogenic	Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia	2018-10-31	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000224376	SCV001250370	pathogenic	not provided	2018-02-01	criteria provided, single submitter	clinical testing
Invitae	RCV000224376	SCV001418698	pathogenic	not provided	2024-01-11	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 334 of the ALPL protein (p.Gly334Asp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatasia (PMID: 8406453, 24569605). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Gly317Asp. ClinVar contains an entry for this variant (Variation ID: 13672). 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%. Experimental studies have shown that this missense change affects ALPL function (PMID: 19500388, 24569605). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV000224376	SCV001826963	pathogenic	not provided	2021-04-23	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek et al., 2016); Published functional studies demonstrate this variant has decreased activity and dominant-negative effects (Fauvert et al., 2009; Hoffman et al., 2014; Del Angel et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 8406453, 33101980, 24569605, 19500388, 32160374, 20301329, 9618260, 9781036, 12638946, 15694177, 22397652)
Blueprint Genetics	RCV000224376	SCV001832370	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276547	SCV002564705	pathogenic	Osteogenesis imperfecta	2020-06-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000786923	SCV004193808	pathogenic	Adult hypophosphatasia	2022-07-30	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV003952356	SCV004772668	pathogenic	ALPL-related condition	2023-11-27	criteria provided, single submitter	clinical testing	The ALPL c.1001G>A variant is predicted to result in the amino acid substitution p.Gly334Asp. This variant is a common pathogenic variant in the Canadian Mennonite population and has been reported in several Mennonite patients with hypophosphatasia (HPP) (Greenberg et al. 1993. PubMed ID: 8406453, reported as p.Gly317Asp). This variant has also been reported in the homozygous or compound heterozygous state in several other unrelated patients with HPP (Orimo et al. 2002. PubMed ID: 12638946; Mornet et al. 1998. PubMed ID: 9781036; Hofmann et al. 2014. PubMed ID: 24569605). Functional studies support its pathogenicity (Fauvert et al. 2009. PubMed ID: 19500388; Hofmann et al. 2014. PubMed ID: 24569605; Del Angel et al. 2020. PubMed ID: 32160374). A different substitution (Gly334Arg), affecting the same amino acid residue, was reported in a patient with mild HPP (Fauvert et al. 2009. PubMed ID: 19500388). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000207270	SCV004803682	pathogenic	Hypophosphatasia	2024-01-23	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1001G>A (p.Gly334Asp, also known as p.Gly317Asp) 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 was absent in 250928 control chromosomes. c.1001G>A has been reported either at a homozygous state or at a compound heterozygous state along with a second pathogenic variant in multiple individuals affected with autosomal recessive Hypophosphatasia (example, DelAngel_2020, Gehring_1999). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in about 6% of normal activity in MDCK II cells (DelAngel_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32160374, 10636450). ClinVar contains an entry for this variant (Variation ID: 13672). Based on the evidence outlined above, the variant was classified as pathogenic.
OMIM	RCV000014663	SCV000034918	pathogenic	Infantile hypophosphatasia	1993-07-01	no assertion criteria provided	literature only
GeneReviews	RCV000207270	SCV000262614	not provided	Hypophosphatasia		no assertion provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000786923	SCV000925824	pathogenic	Adult hypophosphatasia	2018-12-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV000207270	SCV002094083	pathogenic	Hypophosphatasia	2020-10-05	no assertion criteria provided	clinical testing