NM_000478.6(ALPL):c.188G>T (p.Gly63Val) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Aug 5, 2022
Review status:: criteria provided, conflicting classifications

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:: RCV000595916.9

Allele description [Variation Report for NM_000478.6(ALPL):c.188G>T (p.Gly63Val)]

NM_000478.6(ALPL):c.188G>T (p.Gly63Val)

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.188G>T (p.Gly63Val)

HGVS:

NC_000001.11:g.21561103G>T
NG_008940.1:g.56739G>T
NM_000478.6:c.188G>TMANE SELECT
NM_001127501.4:c.23G>T
NM_001177520.3:c.66+358G>T
NM_001369803.2:c.188G>T
NM_001369804.2:c.188G>T
NM_001369805.2:c.188G>T
NP_000469.3:p.Gly63Val
NP_001120973.2:p.Gly8Val
NP_001356732.1:p.Gly63Val
NP_001356733.1:p.Gly63Val
NP_001356734.1:p.Gly63Val
NC_000001.10:g.21887596G>T

Protein change:

G63V

Links:

dbSNP: rs1490668038

NCBI 1000 Genomes Browser:

rs1490668038

Molecular consequence:

NM_001177520.3:c.66+358G>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000478.6:c.188G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.23G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.188G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.188G>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.188G>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

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
SCV000705789	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Uncertain significance (Feb 17, 2017)	germline	clinical testing	Citation Link,
SCV002260415	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Aug 5, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 12815606, 21419245, 11479741, 25731960, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV000705789

Eurofins Ntd Llc (ga)

criteria provided, single submitter

(EGL Classification Definitions 2015)

Uncertain significance
(Feb 17, 2017)

germline

clinical testing

Citation Link,

SCV002260415

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Aug 5, 2022)

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	2	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene.

Spentchian M, Merrien Y, Herasse M, Dobbie Z, Gläser D, Holder SE, Ivarsson SA, Kostiner D, Mansour S, Norman A, Roth J, Stipoljev F, Taillemite JL, van der Smagt JJ, Serre JL, Simon-Bouy B, Taillandier A, Mornet E.

Hum Mutat. 2003 Jul;22(1):105-6.

PubMed [citation]

PMID:: 12815606

Functional characterization of a novel mutation localized in the start codon of the tissue-nonspecific alkaline phosphatase gene.

Mentrup B, Marschall C, Barvencik F, Amling M, Plendl H, Jakob F, Beck C.

Bone. 2011 Jun 1;48(6):1401-8. doi: 10.1016/j.bone.2011.03.676. Epub 2011 Mar 16.

PubMed [citation]

PMID:: 21419245

See all PubMed Citations (5)

Details of each submission

From Eurofins Ntd Llc (ga), SCV000705789.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	2	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		2	not provided	not provided	not provided

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002260415.3

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

Description

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. 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. This variant disrupts the p.Gly63 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 12815606), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Experimental studies have shown that this missense change affects ALPL function (PMID: 11479741, 21419245). ClinVar contains an entry for this variant (Variation ID: 500024). This variant is also known as p.G46V. This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11479741, 25731960). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 63 of the ALPL protein (p.Gly63Val).

#	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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