NM_000478.6(ALPL):c.119C>T (p.Ala40Val) AND Hypophosphatasia

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Oct 15, 2020
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV001264416.3

Allele description [Variation Report for NM_000478.6(ALPL):c.119C>T (p.Ala40Val)]

NM_000478.6(ALPL):c.119C>T (p.Ala40Val)

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.119C>T (p.Ala40Val)

HGVS:

NC_000001.11:g.21560683C>T
NG_008940.1:g.56319C>T
NM_000478.6:c.119C>TMANE SELECT
NM_001127501.4:c.-47C>T
NM_001177520.3:c.4C>T
NM_001369803.2:c.119C>T
NM_001369804.2:c.119C>T
NM_001369805.2:c.119C>T
NP_000469.3:p.Ala40Val
NP_001170991.1:p.Pro2Ser
NP_001356732.1:p.Ala40Val
NP_001356733.1:p.Ala40Val
NP_001356734.1:p.Ala40Val
NC_000001.10:g.21887176C>T
NM_000478.4:c.119C>T
NM_000478.5:c.119C>T

Protein change:

A40V

Links:

dbSNP: rs770093969

NCBI 1000 Genomes Browser:

rs770093969

Molecular consequence:

NM_001127501.4:c.-47C>T - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_000478.6:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.4C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.119C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Hypophosphatasia
Synonyms:: Phosphoethanol-aminuria
Identifiers:: MONDO: MONDO:0018570; MedGen: C0020630

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001442547	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 15, 2020)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 24276437, 9781036, 11438998, 10679946, 22397652, 10332035 Citation Link,
SCV002094048	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 28, 2021)	germline	clinical testing

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001442547

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Oct 15, 2020)

germline

clinical testing

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

Citation Link,

SCV002094048

Natera, Inc.

no assertion criteria provided

Pathogenic
(Sep 28, 2021)

germline

clinical testing

Help

Summary from all submissions

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

Citations

PubMed

Clinical and genetic aspects of hypophosphatasia in Japanese patients.

Taketani T, Onigata K, Kobayashi H, Mushimoto Y, Fukuda S, Yamaguchi S.

Arch Dis Child. 2014 Mar;99(3):211-5. doi: 10.1136/archdischild-2013-305037. Epub 2013 Nov 25.

PubMed [citation]

PMID:: 24276437

Identification of fifteen novel mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in European patients with severe hypophosphatasia.

Mornet E, Taillandier A, Peyramaure S, Kaper F, Muller F, Brenner R, Bussière P, Freisinger P, Godard J, Le Merrer M, Oury JF, Plauchu H, Puddu R, Rival JM, Superti-Furga A, Touraine RL, Serre JL, Simon-Bouy B.

Eur J Hum Genet. 1998 Jul-Aug;6(4):308-14.

PubMed [citation]

PMID:: 9781036

See all PubMed Citations (6)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001442547.1

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

Description

Variant summary: ALPL c.119C>T (p.Ala40Val) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251466 control chromosomes. c.119C>T has been reported in the literature in multiple individuals affected with Hypophosphatasia (e.g. Mornet_1998, Taillandier_2000, Taillandier_2001, Whyte_2012, Taketani_2014). 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 <10% of normal activity (Zurutuza_1999). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was 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 Natera, Inc., SCV002094048.1

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

Last Updated: Oct 8, 2024

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