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

Clinical significance:Pathogenic/Likely pathogenic (Last evaluated: Jul 1, 2021)

Review status:2 stars out of maximum of 4 stars

criteria provided, multiple submitters, no conflicts

Based on:
4 submissions [Details]
Record status:
current
Accession:
RCV000710510.5

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)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000332907EGL Genetic Diagnostics, Eurofins Clinical Diagnosticscriteria provided, single submitter
Likely pathogenic
(Jul 16, 2015)
germlineclinical testing

Citation Link,

SCV000840747Athena Diagnostics Inccriteria provided, single submitter
Likely pathogenic
(Jul 17, 2018)
germlineclinical testing

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

SCV001405222Invitaecriteria provided, single submitter
Pathogenic
(Oct 19, 2020)
germlineclinical testing

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

SCV001756506GeneDxcriteria provided, single submitter
Pathogenic
(Jul 1, 2021)
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 (7)

Details of each submission

From EGL Genetic Diagnostics, Eurofins Clinical Diagnostics, 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 Inc, 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 Invitae, SCV001405222.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (6)

Description

This sequence change replaces asparagine with serine at codon 417 of the ALPL protein (p.Asn417Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs121918014, ExAC 0.009%). This variant has been observed to segregate with hypophosphatasia in a family (PMID: 25731960) and has also been observed in individuals with hypophosphatasia (PMID: 11745997, 25731960, 27998428). This variant is also known as p.Asn400Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 13679). This variant has been reported to affect ALPL protein function (PMID: 19500388; 23688511). For these reasons, this allele has been classified as Pathogenic.

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

From GeneDx, SCV001756506.1

#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 (Fauvert et al., 2009); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 27535533, 32160374, 29160013, 28000043, 29405932, 29236161, 28939177, 11745997, 28401263, 19232125, 21956185, 27998428, 19500388, 23688511)

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

Last Updated: Aug 17, 2021

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