NM_000478.6(ALPL):c.211C>T (p.Arg71Cys) AND not provided

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 28, 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:: RCV001851857.6

Allele description [Variation Report for NM_000478.6(ALPL):c.211C>T (p.Arg71Cys)]

NM_000478.6(ALPL):c.211C>T (p.Arg71Cys)

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.211C>T (p.Arg71Cys)

Other names:

R54C

HGVS:

NC_000001.11:g.21561126C>T
NG_008940.1:g.56762C>T
NM_000478.6:c.211C>TMANE SELECT
NM_001127501.4:c.46C>T
NM_001177520.3:c.66+381C>T
NM_001369803.2:c.211C>T
NM_001369804.2:c.211C>T
NM_001369805.2:c.211C>T
NP_000469.3:p.Arg71Cys
NP_001120973.2:p.Arg16Cys
NP_001356732.1:p.Arg71Cys
NP_001356733.1:p.Arg71Cys
NP_001356734.1:p.Arg71Cys
NC_000001.10:g.21887619C>T
NM_000478.4:c.211C>T
NM_000478.5:c.211C>T
P05186:p.Arg71Cys

Protein change:

R16C; ARG54CYS

Links:

UniProtKB: P05186#VAR_006149; OMIM: 171760.0002; dbSNP: rs121918001

NCBI 1000 Genomes Browser:

rs121918001

Molecular consequence:

NM_001177520.3:c.66+381C>T - intron variant - [Sequence Ontology: SO:0001627]
NM_000478.6:c.211C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.46C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.211C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.211C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.211C>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
SCV002242992	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Dec 28, 2023)	germline	clinical testing	PubMed (9) [See all records that cite these PMIDs] 1409720, 31600233, 10839996, 11438998, 22322541, 22397652, 25731960, 31760938, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002242992

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Pathogenic
(Dec 28, 2023)

germline

clinical testing

PubMed (9)
[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

Different missense mutations at the tissue-nonspecific alkaline phosphatase gene locus in autosomal recessively inherited forms of mild and severe hypophosphatasia.

Henthorn PS, Raducha M, Fedde KN, Lafferty MA, Whyte MP.

Proc Natl Acad Sci U S A. 1992 Oct 15;89(20):9924-8.

PubMed [citation]

PMID:: 1409720
PMCID:: PMC50246

Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types.

Okawa R, Kokomoto K, Kitaoka T, Kubota T, Watanabe A, Taketani T, Michigami T, Ozono K, Nakano K.

PLoS One. 2019;14(10):e0222931. doi: 10.1371/journal.pone.0222931.

PubMed [citation]

PMID:: 31600233
PMCID:: PMC6786601

See all PubMed Citations (9)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002242992.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (9)

Description

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 71 of the ALPL protein (p.Arg71Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of hypophosphatasia (PMID: 1409720, 31600233). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as Arg54Cys. ClinVar contains an entry for this variant (Variation ID: 13663). 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: 10839996). This variant disrupts the p.Arg71 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11438998, 22322541, 22397652, 25731960, 31760938). 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: Oct 13, 2024

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