U.S. flag

An official website of the United States government

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:
2

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

Recent activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...

Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000332907Eurofins Ntd Llc (ga)
criteria provided, single submitter

(EGL Classification Definitions 2015)
Likely pathogenic
(Jul 16, 2015)
germlineclinical testing

Citation Link,

SCV000840747Athena Diagnostics
criteria provided, single submitter

(Athena Diagnostics Criteria)
Likely pathogenic
(Jul 17, 2018)
germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

SCV001405222Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))
Pathogenic
(Jan 25, 2024)
germlineclinical testing

PubMed (6)
[See all records that cite these PMIDs]

SCV001756506GeneDx
criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)
Pathogenic
(Jul 8, 2024)
germlineclinical testing

Citation Link,

SCV002018162Revvity Omics, Revvity
criteria provided, single submitter

(ACMG Guidelines, 2015)
Pathogenic
(Feb 23, 2021)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV004563671ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
criteria provided, single submitter

(ARUP Molecular Germline Variant Investigation Process 2024)
Pathogenic
(Jun 20, 2023)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknown2not providednot providednot providednot providedclinical 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
See all PubMed Citations (8)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000332907.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided2not providednot providedclinical testingnot provided
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot provided2not providednot providednot provided

From Athena Diagnostics, SCV000840747.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (4)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV001756506.4

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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)

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From Revvity Omics, Revvity, SCV002018162.3

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

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

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot 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.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Sep 29, 2024