NM_000478.6(ALPL):c.658G>A (p.Gly220Arg) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Oct 17, 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:: RCV001236036.14

Allele description [Variation Report for NM_000478.6(ALPL):c.658G>A (p.Gly220Arg)]

NM_000478.6(ALPL):c.658G>A (p.Gly220Arg)

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.658G>A (p.Gly220Arg)

HGVS:

NC_000001.11:g.21568113G>A
NG_008940.1:g.63749G>A
NM_000478.6:c.658G>AMANE SELECT
NM_001127501.4:c.493G>A
NM_001177520.3:c.427G>A
NM_001369803.2:c.658G>A
NM_001369804.2:c.658G>A
NM_001369805.2:c.658G>A
NP_000469.3:p.Gly220Arg
NP_001120973.2:p.Gly165Arg
NP_001170991.1:p.Gly143Arg
NP_001356732.1:p.Gly220Arg
NP_001356733.1:p.Gly220Arg
NP_001356734.1:p.Gly220Arg
NC_000001.10:g.21894606G>A
NM_000478.4:c.658G>A
NM_000478.5:c.658G>A

Protein change:

G143R

Links:

dbSNP: rs747488546

NCBI 1000 Genomes Browser:

rs747488546

Molecular consequence:

NM_000478.6:c.658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.493G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.427G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.658G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.658G>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
SCV001408748	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Oct 17, 2023)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 25731960, 12815606, 22394703, 22397652, 28663156, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001408748

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Oct 17, 2023)

germline

clinical testing

PubMed (6)
[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

Hypophosphatasia: validation and expansion of the clinical nosology for children from 25 years experience with 173 pediatric patients.

Whyte MP, Zhang F, Wenkert D, McAlister WH, Mack KE, Benigno MC, Coburn SP, Wagy S, Griffin DM, Ericson KL, Mumm S.

Bone. 2015 Jun;75:229-39. doi: 10.1016/j.bone.2015.02.022. Epub 2015 Feb 27.

PubMed [citation]

PMID:: 25731960

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

See all PubMed Citations (6)

Details of each submission

From Invitae, SCV001408748.5

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

Description

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 220 of the ALPL protein (p.Gly220Arg). This variant is present in population databases (rs747488546, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 22397652, 25731960). ClinVar contains an entry for this variant (Variation ID: 554408). 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. This variant disrupts the p.Gly220 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12815606, 22394703, 22397652, 28663156). 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: May 1, 2024

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