NM_000478.6(ALPL):c.118G>A (p.Ala40Thr) AND not provided

Germline classification:: Likely pathogenic (1 submission)
Last evaluated:: Dec 9, 2023
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:: RCV001961545.6

Allele description [Variation Report for NM_000478.6(ALPL):c.118G>A (p.Ala40Thr)]

NM_000478.6(ALPL):c.118G>A (p.Ala40Thr)

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.118G>A (p.Ala40Thr)

HGVS:

NC_000001.11:g.21560682G>A
NG_008940.1:g.56318G>A
NM_000478.6:c.118G>AMANE SELECT
NM_001127501.4:c.-48G>A
NM_001177520.3:c.3G>A
NM_001369803.2:c.118G>A
NM_001369804.2:c.118G>A
NM_001369805.2:c.118G>A
NP_000469.3:p.Ala40Thr
NP_001170991.1:p.Met1Ile
NP_001356732.1:p.Ala40Thr
NP_001356733.1:p.Ala40Thr
NP_001356734.1:p.Ala40Thr
NC_000001.10:g.21887175G>A

Protein change:

A40T

Links:

dbSNP: rs1455153945

NCBI 1000 Genomes Browser:

rs1455153945

Molecular consequence:

NM_001127501.4:c.-48G>A - 5 prime UTR variant - [Sequence Ontology: SO:0001623]
NM_001177520.3:c.3G>A - initiator_codon_variant - [Sequence Ontology: SO:0001582]
NM_000478.6:c.118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.3G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.118G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.118G>A - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002248709	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Dec 9, 2023)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 11438998, 15660230, 22397652, 24276437, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002248709

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Dec 9, 2023)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

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

Twelve novel mutations in the tissue-nonspecific alkaline phosphatase gene (ALPL) in patients with various forms of hypophosphatasia.

Taillandier A, Lia-Baldini AS, Mouchard M, Robin B, Muller F, Simon-Bouy B, Serre JL, Bera-Louville A, Bonduelle M, Eckhardt J, Gaillard D, Myhre AG, Körtge-Jung S, Larget-Piet L, Malou E, Sillence D, Temple IK, Viot G, Mornet E.

Hum Mutat. 2001;18(1):83-4.

PubMed [citation]

PMID:: 11438998

Common mutations F310L and T1559del in the tissue-nonspecific alkaline phosphatase gene are related to distinct phenotypes in Japanese patients with hypophosphatasia.

Michigami T, Uchihashi T, Suzuki A, Tachikawa K, Nakajima S, Ozono K.

Eur J Pediatr. 2005 May;164(5):277-82. Epub 2005 Jan 20.

PubMed [citation]

PMID:: 15660230

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002248709.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (5)

Description

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 40 of the ALPL protein (p.Ala40Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with hypophosphatasia (Invitae). ClinVar contains an entry for this variant (Variation ID: 1469393). 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%. This variant disrupts the p.Ala40 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11438998, 15660230, 22397652, 24276437). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely 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

Last Updated: Sep 29, 2024

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