NM_000478.6(ALPL):c.212G>A (p.Arg71His) AND not provided

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Dec 2, 2023
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV001382221.7

Allele description [Variation Report for NM_000478.6(ALPL):c.212G>A (p.Arg71His)]

NM_000478.6(ALPL):c.212G>A (p.Arg71His)

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.212G>A (p.Arg71His)

HGVS:

NC_000001.11:g.21561127G>A
NG_008940.1:g.56763G>A
NM_000478.6:c.212G>AMANE SELECT
NM_001127501.4:c.47G>A
NM_001177520.3:c.66+382G>A
NM_001369803.2:c.212G>A
NM_001369804.2:c.212G>A
NM_001369805.2:c.212G>A
NP_000469.3:p.Arg71His
NP_001120973.2:p.Arg16His
NP_001356732.1:p.Arg71His
NP_001356733.1:p.Arg71His
NP_001356734.1:p.Arg71His
NC_000001.10:g.21887620G>A
NM_000478.4:c.212G>A

Protein change:

R16H

Links:

dbSNP: rs121918003

NCBI 1000 Genomes Browser:

rs121918003

Molecular consequence:

NM_001177520.3:c.66+382G>A - intron variant - [Sequence Ontology: SO:0001627]
NM_000478.6:c.212G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.47G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.212G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.212G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.212G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001580892	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 2, 2023)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 11438998, 22322541, 22397652, 25731960, 31760938, 19500388, 1409720, 10839996, 11760847, 28127875, 28492532
SCV002013355	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Jul 5, 2023)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001580892

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 2, 2023)

germline

clinical testing

PubMed (11)
[See all records that cite these PMIDs]

SCV002013355

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Pathogenic
(Jul 5, 2023)

germline

clinical testing

Citation Link

Help

Summary from all submissions

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

"Atypical femoral fractures" during bisphosphonate exposure in adult hypophosphatasia.

Sutton RA, Mumm S, Coburn SP, Ericson KL, Whyte MP.

J Bone Miner Res. 2012 May;27(5):987-94. doi: 10.1002/jbmr.1565.

PubMed [citation]

PMID:: 22322541

See all PubMed Citations (11)

Details of each submission

From Invitae, SCV001580892.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (11)

Description

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 71 of the ALPL protein (p.Arg71His). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with less severe presentations of hypophosphatasia and autosomal recessive infantile or childhood-onset hypophosphatasia (PMID: 11438998, 19500388, 22322541, 22397652, 25731960, 31760938). This variant is also known as p.Arg54His. ClinVar contains an entry for this variant (Variation ID: 1070177). 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.Arg71 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been observed in individuals with ALPL-related conditions (PMID: 1409720, 10839996, 11760847, 28127875), which suggests that this may be a clinically significant amino acid residue. 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

From GeneDx, SCV002013355.3

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

Description

Published functional studies demonstrate p.(R71H) results in decreased alkaline phosphatase activity via a dominant-negative effect (Del Angel et al., 2020; Fauvert et al., 2009); Observed in heterozygous state with no other ALPL variants in individuals with adult odonto hypophosphatasia (Fauvert et al., 2009; Del Angel et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22322541, 11438998, 32160374, 22397652, 32973344, 25731960, 12674323, 19500388)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 17, 2024

ClinVar

Relating variation to medicine