Submissions for variant NM_000478.6(ALPL):c.1250A>G (p.Asn417Ser)

gnomAD frequency: 0.00006  dbSNP: rs121918014

Total submissions: 17

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000710510	SCV000332907	likely pathogenic	not provided	2015-07-16	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV000710510	SCV000840747	likely pathogenic	not provided	2018-07-17	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001194283	SCV001363683	pathogenic	Hypophosphatasia	2019-08-05	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1250A>G (p.Asn417Ser) results in a conservative amino acid change located in the Crown domain (Simon-Bouy_2008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes (gnomAD). c.1250A>G has been reported in the literature as a single heterozygous variant (i.e. no other variants detected) in multiple individuals with features of mild HPP (odontohypophosphatasia, adult and childhood hypophosphatasia) but also in at least 2 parents that were carriers of the variant without any reported symptoms (Fauvert_2009, Reibel_2009, Whyte_2015). It has also been reported in compound heterozygous state with other pathogenic variants in patients affected with severe perinatal or severe childhood hypophosphatasia (Sergi_2001, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. Using a cell system Fauvert et al reported that this variant has a dominant negative effect (Fauvert_2009) on wild-type enzymatic activity. In addition, Sultana et al performed several functional experiments using an in vitro system and concluded that a complete loss of ALP enzymatic activity resulting from the disruption of its functional dimer structure may represent the molecular basis of HPP associated with ALPL N417S (Sultana_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000710510	SCV001405222	pathogenic	not provided	2024-12-24	criteria provided, single submitter	clinical testing	This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 417 of the ALPL protein (p.Asn417Ser). This variant is present in population databases (rs121918014, gnomAD 0.006%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11745997, 25731960, 27998428). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as p.Asn400Ser. ClinVar contains an entry for this variant (Variation ID: 13679). 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, 23688511). For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253058	SCV001428580	likely pathogenic	Adult hypophosphatasia	2020-11-30	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV001253058	SCV001711955	pathogenic	Adult hypophosphatasia	2021-05-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000710510	SCV001756506	pathogenic	not provided	2024-07-08	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that N417S exhibits a dominant effect on the ALPL protein (PMID: 19500388); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 34633109, 21956185, 29405932, 23688511, 11745997, 19500388, 27998428, 19232125, 28401263, 28939177, 29236161, 28000043, 29160013, 32160374, 28436937, 33069919, 25731960, 37993691, 36444396, 34258332, 33549410, 35878747, 34662886, 37422472)
Revvity Omics, Revvity	RCV000710510	SCV002018162	pathogenic	not provided	2021-02-23	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV001253058	SCV004194385	pathogenic	Adult hypophosphatasia	2024-03-28	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710510	SCV004563671	pathogenic	not provided	2023-06-20	criteria provided, single submitter	clinical testing	The ALPL c.1250A>G; p.Asn417Ser variant (rs121918014) is reported in the literature in numerous heterozygous individuals affected with hypophosphatasia (Durrough 2021, Fauvert 2009, Hepp 2021, Taillandier 2018), and in one compound heterozygous case affected with perinatal hypophosphatasia (Sergi 2001). This variant is also reported in ClinVar (Variation ID: 13679), and is found in the non-Finnish European population with an allele frequency of 0.006% (8/129126 alleles) in the Genome Aggregation Database. In vitro functional analyses demonstrate reduced ALP enzymatic activity and exhibits a dominant negative effect on wild-type enzymatic activity (Del Angel 2020, Fauvert 2009, Sultana 2013). Computational analyses also predict that this variant is deleterious (REVEL: 0.81). Based on available information, this variant is considered to be pathogenic. References: Del Angel G et al. Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia. Hum Mutat. 2020 Jul;41(7):1250-1262. PMID: 32160374. Durrough C et al. Characterization of physical, functional, and cognitive performance in 15 adults with hypophosphatasia. Bone. 2021 Jan;142:115695. PMID: 33069919. Fauvert D et al. Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles. BMC Med Genet. 2009 Jun 6;10:51. PMID: 19500388. Hepp N et al. Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark. Bone Rep. 2021 Jun 28;15:101101. PMID: 34258332. Sergi C et al. Perinatal hypophosphatasia: radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Am J Med Genet. 2001 Oct 15;103(3):235-40. PMID: 11745997. Sultana S et al. An asparagine at position 417 of tissue-nonspecific alkaline phosphatase is essential for its structure and function as revealed by analysis of the N417S mutation associated with severe hypophosphatasia. Mol Genet Metab. 2013 Jul;109(3):282-8. PMID: 23688511. Taillandier A et al. Genetic analysis of adults heterozygous for ALPL mutations. J Bone Miner Metab. 2018 Nov;36(6):723-733. PMID: 29236161.
Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	RCV004719646	SCV005326352	pathogenic	Childhood hypophosphatasia		criteria provided, single submitter	clinical testing	The p.Asn417Ser variant detected in this individual is predicted to substitute the asparagine at amino acid position 417 with a serine in the crown domain of the protein. The majority of in silico tools predict this variant is damaging, and functional studies have demonstrated that the p.Asn417Ser variant exerts a dominant negative effect on TNSALP, resulting in lack of dimer formation and reduced activity (PMID: 19500388, PMID: 236885113, PMID: 32160374). This variant is present in large population studies at low frequencies (50 of 1,613,808 alleles, no homozygotes, gnomAD v4.0.0).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001194283	SCV005399304	pathogenic	Hypophosphatasia	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0104 - Dominant Negative is a mechanism of disease for this gene. Functional studies have shown this variant to have a dominant negative effect (PMID: 19500388). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. Severe forms of hypophosphatasia (perinatal and infantile) are generally associated with autosomal recessive disease, while the milder forms of hypophosphatasia (childhood, adult and odonto) have been associated with both autosomal dominant and recessive disease (PMID: 19500388, 23688511). (N) 0112 - Variants in this gene are known to have reduced penetrance. Reduced penetrance and variable expressivity have been reported in patients (PMID: 31760938). (N) 0200 - Variant is predicted to result in a missense amino acid change from asparagine to serine (exon 11). (N) 0251 - Variant is heterozygous. (N) 0302 - Variant is present in gnomAD <0.001 (8 heterozygotes, 0 homozygotes). (P) 0501 - Missense variant consistently predicted to be damaging by multiple in-silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (Crown domain; PMID: 18925618, 23688511). (N) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0801 – Very strong previous evidence of pathogenicity in unrelated individuals. This variant has been previously reported in heterozygous patients with adult hypophosphatasia or odontohypophosphatasia (PMID: 19500388, 28401263, 28436937) and in compound heterozygous state in association with perinatal lethal hypophosphatasia (ClinVar, PMID: 11745997, 18925618). (P) 1002 - Moderate functional evidence supporting abnormal protein function. Functional studies showed this variant impairs protein assembly and function (PMID: 23688511). (P) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics	RCV005016265	SCV005644646	pathogenic	Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia	2024-05-02	criteria provided, single submitter	clinical testing
OMIM	RCV000169778	SCV000034927	pathogenic	Perinatal lethal hypophosphatasia	2001-10-15	no assertion criteria provided	literature only
Counsyl	RCV000014672	SCV000221154	pathogenic	Infantile hypophosphatasia	2018-10-03	no assertion criteria provided	clinical testing
GenomeConnect - Invitae Patient Insights Network	RCV001194283	SCV001749798	not provided	Hypophosphatasia		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 11-16-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.
PreventionGenetics, part of Exact Sciences	RCV004739306	SCV005349953	pathogenic	ALPL-related disorder	2024-07-21	no assertion criteria provided	clinical testing	The ALPL c.1250A>G variant is predicted to result in the amino acid substitution p.Asn417Ser. This variant has been reported in multiple patients with autosomal dominant or recessive hypophosphatasia, and also in patients with odontohypophosphatasia (Sergi et al. 2001. PubMed ID: 11745997; Fauvert et al. 2009. PubMed ID: 19500388; Sultana et al. 2013. PubMed ID: 23688511; Taillandier et al. 2017. PubMed ID: 29236161). Additionally, this variant was shown to confer ~5% enzyme activity compared to wild-type (Del Angel et al 2020. PubMed ID: 32160374). This variant is reported in 0.0062% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic.