NM_000478.6(ALPL):c.1250A>G (p.Asn417Ser) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Jul 8, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000710510.23

Allele description [Variation Report for NM_000478.6(ALPL):c.1250A>G (p.Asn417Ser)]

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

Gene:

ALPL:alkaline phosphatase, biomineralization associated [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

1p36.12

Genomic location:

Preferred name:

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

Other names:

N400S

HGVS:

NC_000001.11:g.21576582A>G
NG_008940.1:g.72218A>G
NM_000478.6:c.1250A>GMANE SELECT
NM_001127501.4:c.1085A>G
NM_001177520.3:c.1019A>G
NM_001369803.2:c.1250A>G
NM_001369804.2:c.1250A>G
NM_001369805.2:c.1250A>G
NP_000469.3:p.Asn417Ser
NP_001120973.2:p.Asn362Ser
NP_001170991.1:p.Asn340Ser
NP_001356732.1:p.Asn417Ser
NP_001356733.1:p.Asn417Ser
NP_001356734.1:p.Asn417Ser
NC_000001.10:g.21903075A>G
NM_000478.4:c.1250A>G
NM_000478.5:c.1250A>G
P05186:p.Asn417Ser

Protein change:

N340S; ASN400SER

Links:

UniProtKB: P05186#VAR_025937; OMIM: 171760.0017; dbSNP: rs121918014

NCBI 1000 Genomes Browser:

rs121918014

Molecular consequence:

NM_000478.6:c.1250A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.1085A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.1019A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.1250A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.1250A>G - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.1250A>G - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000332907	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Jul 16, 2015)	germline	clinical testing	Citation Link,
SCV000840747	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics Criteria)	Likely pathogenic (Jul 17, 2018)	germline	clinical testing	PubMed (4) [See all records that cite these PMIDs] 11745997, 19500388, 23688511, 26467025
SCV001405222	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 25, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11745997, 25731960, 27998428, 19500388, 23688511, 28492532
SCV001756506	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 8, 2024)	germline	clinical testing	Citation Link,
SCV002018162	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 23, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004563671	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024)	Pathogenic (Jun 20, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.

Karbassi I, Maston GA, Love A, DiVincenzo C, Braastad CD, Elzinga CD, Bright AR, Previte D, Zhang K, Rowland CM, McCarthy M, Lapierre JL, Dubois F, Medeiros KA, Batish SD, Jones J, Liaquat K, Hoffman CA, Jaremko M, Wang Z, Sun W, Buller-Burckle A, et al.

Hum Mutat. 2016 Jan;37(1):127-34. doi: 10.1002/humu.22918. Epub 2015 Oct 29.

PubMed [citation]

PMID:: 26467025
PMCID:: PMC4737317

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.

Sergi C, Mornet E, Troeger J, Voigtlaender T.

Am J Med Genet. 2001 Oct 15;103(3):235-40.

PubMed [citation]

PMID:: 11745997

See all PubMed Citations (8)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000332907.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		2	not provided	not provided	not provided

From Athena Diagnostics, SCV000840747.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (4)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001405222.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

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). 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, 23688511). For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From GeneDx, SCV001756506.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002018162.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV004563671.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 13, 2024

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