NM_000478.6(ALPL):c.1375G>T (p.Val459Leu) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jan 22, 2024
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:: RCV001225796.8

Allele description [Variation Report for NM_000478.6(ALPL):c.1375G>T (p.Val459Leu)]

NM_000478.6(ALPL):c.1375G>T (p.Val459Leu)

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.1375G>T (p.Val459Leu)

HGVS:

NC_000001.11:g.21577448G>T
NG_008940.1:g.73084G>T
NM_000478.6:c.1375G>TMANE SELECT
NM_001127501.4:c.1210G>T
NM_001177520.3:c.1144G>T
NM_001369803.2:c.1375G>T
NM_001369804.2:c.1375G>T
NM_001369805.2:c.1375G>T
NP_000469.3:p.Val459Leu
NP_001120973.2:p.Val404Leu
NP_001170991.1:p.Val382Leu
NP_001356732.1:p.Val459Leu
NP_001356733.1:p.Val459Leu
NP_001356734.1:p.Val459Leu
NC_000001.10:g.21903941G>T
NM_000478.4:c.1375G>T
NM_000478.5:c.1375G>T

Protein change:

V382L

Links:

dbSNP: rs1054159992

NCBI 1000 Genomes Browser:

rs1054159992

Molecular consequence:

NM_000478.6:c.1375G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.1210G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.1144G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.1375G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.1375G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.1375G>T - 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
SCV001398088	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 22, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 19500388, 11438998, 27699270, 31707452, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001398088

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Jan 22, 2024)

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

Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles.

Fauvert D, Brun-Heath I, Lia-Baldini AS, Bellazi L, Taillandier A, Serre JL, de Mazancourt P, Mornet E.

BMC Med Genet. 2009 Jun 6;10:51. doi: 10.1186/1471-2350-10-51.

PubMed [citation]

PMID:: 19500388
PMCID:: PMC2702372

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

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV001398088.5

#	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 valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 459 of the ALPL protein (p.Val459Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant hypophosphatasia and/or hypophosphatasia (PMID: 19500388; Invitae). ClinVar contains an entry for this variant (Variation ID: 558598). 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). This variant disrupts the p.Val459 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11438998, 27699270, 31707452). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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

Last Updated: Sep 29, 2024

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