NM_000478.6(ALPL):c.454C>T (p.Arg152Cys) AND not provided

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Jan 18, 2024
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:: RCV001973364.7

Allele description [Variation Report for NM_000478.6(ALPL):c.454C>T (p.Arg152Cys)]

NM_000478.6(ALPL):c.454C>T (p.Arg152Cys)

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.454C>T (p.Arg152Cys)

HGVS:

NC_000001.11:g.21563266C>T
NG_008940.1:g.58902C>T
NM_000478.6:c.454C>TMANE SELECT
NM_001127501.4:c.289C>T
NM_001177520.3:c.223C>T
NM_001369803.2:c.454C>T
NM_001369804.2:c.454C>T
NM_001369805.2:c.454C>T
NP_000469.3:p.Arg152Cys
NP_001120973.2:p.Arg97Cys
NP_001170991.1:p.Arg75Cys
NP_001356732.1:p.Arg152Cys
NP_001356733.1:p.Arg152Cys
NP_001356734.1:p.Arg152Cys
NC_000001.10:g.21889759C>T
NM_000478.4:c.454C>T
NM_000478.5:c.454C>T
NM_000478.6:c.454C>T

Protein change:

R152C

Links:

dbSNP: rs200621180

NCBI 1000 Genomes Browser:

rs200621180

Molecular consequence:

NM_000478.6:c.454C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.289C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.223C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.454C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.454C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.454C>T - 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
SCV002256239	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 18, 2024)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 22014174, 23791648, 32066479, 32160374, 28492532
SCV002588071	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Uncertain significance (Oct 26, 2022)	germline	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002256239

Labcorp Genetics (formerly Invitae), Labcorp

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Likely pathogenic
(Jan 18, 2024)

germline

clinical testing

PubMed (5)
[See all records that cite these PMIDs]

SCV002588071

GeneDx

criteria provided, single submitter

(GeneDx Variant Classification Process June 2021)

Uncertain significance
(Oct 26, 2022)

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

Correction of hypophosphatasia-associated mineralization deficiencies in vitro by phosphate/pyrophosphate modulation in periodontal ligament cells.

Rodrigues TL, Foster BL, Silverio KG, Martins L, Casati MZ, Sallum EA, Somerman MJ, Nociti FH Jr.

J Periodontol. 2012 May;83(5):653-63. doi: 10.1902/jop.2011.110310. Epub 2011 Oct 20.

PubMed [citation]

PMID:: 22014174
PMCID:: PMC3871996

Novel ALPL genetic alteration associated with an odontohypophosphatasia phenotype.

Martins L, Rodrigues TL, Ribeiro MM, Saito MT, Giorgetti AP, Casati MZ, Sallum EA, Foster BL, Somerman MJ, Nociti FH Jr.

Bone. 2013 Oct;56(2):390-7. doi: 10.1016/j.bone.2013.06.010. Epub 2013 Jun 19.

PubMed [citation]

PMID:: 23791648
PMCID:: PMC3872001

See all PubMed Citations (5)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002256239.3

#	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 arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 152 of the ALPL protein (p.Arg152Cys). This variant is present in population databases (rs200621180, gnomAD 0.002%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 22014174, 23791648, 32066479, 32160374). ClinVar contains an entry for this variant (Variation ID: 1470828). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ALPL protein function. Experimental studies have shown that this missense change affects ALPL function (PMID: 32160374). 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.

#	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, SCV002588071.2

#	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 suggest a damaging effect (mild reduction of activity, no additional functional studies (Del Angel et al., 2020); This variant is associated with the following publications: (PMID: 22014174, 32160374, 28127875, 35320273, 32066479, 31793067, 23791648)

#	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: Sep 29, 2024

ClinVar

Relating variation to medicine