NM_000478.6(ALPL):c.550C>T (p.Arg184Trp) AND Hypophosphatasia

Germline classification:: Pathogenic (3 submissions)
Last evaluated:: Dec 8, 2022
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:: RCV001730702.3

Allele description [Variation Report for NM_000478.6(ALPL):c.550C>T (p.Arg184Trp)]

NM_000478.6(ALPL):c.550C>T (p.Arg184Trp)

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.550C>T (p.Arg184Trp)

Other names:

p.Arg184Trp

HGVS:

NC_000001.11:g.21564118C>T
NG_008940.1:g.59754C>T
NM_000478.6:c.550C>TMANE SELECT
NM_001127501.4:c.385C>T
NM_001177520.3:c.319C>T
NM_001369803.2:c.550C>T
NM_001369804.2:c.550C>T
NM_001369805.2:c.550C>T
NP_000469.3:p.Arg184Trp
NP_001120973.2:p.Arg129Trp
NP_001170991.1:p.Arg107Trp
NP_001356732.1:p.Arg184Trp
NP_001356733.1:p.Arg184Trp
NP_001356734.1:p.Arg184Trp
NC_000001.10:g.21890611C>T
NM_000478.4:c.550C>T
NM_000478.5:c.550C>T

Protein change:

R107W

Links:

dbSNP: rs763159520

NCBI 1000 Genomes Browser:

rs763159520

Molecular consequence:

NM_000478.6:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.385C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.319C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.550C>T - missense variant - [Sequence Ontology: SO:0001583]

Observations:

Condition(s)

Name:: Hypophosphatasia
Synonyms:: Phosphoethanol-aminuria
Identifiers:: MONDO: MONDO:0018570; MedGen: C0020630

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001981524	Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002819339	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 8, 2022)	germline	clinical testing	PubMed (11) [See all records that cite these PMIDs] 19500388, 25731960, 24276437, 19232125, 31600233, 32160374, 10332035, 33814268, 26432670, 33549410, 30049651 Citation Link,
SCV004174856	JKU Lab, Dept of Paediatrics, Johannes Kepler University	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 4, 2022)	germline	clinical testing	PubMed (5) [See all records that cite these PMIDs] 26432670, 31600233, 32160374, 25731960, 25741868

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001981524

Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Sep 15, 2021)

germline

clinical testing

PubMed (1)
[See all records that cite this PMID]

SCV002819339

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 8, 2022)

germline

clinical testing

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

Citation Link,

SCV004174856

JKU Lab, Dept of Paediatrics, Johannes Kepler University

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Mar 4, 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	yes	1	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

Mild forms of hypophosphatasia mostly result from dominant negative effect of severe alleles or from compound heterozygosity for severe and moderate alleles.

Fauvert D, Brun-Heath I, Lia-Baldini AS, Bellazi L, Taillandier A, Serre JL, de Mazancourt P, Mornet E.

BMC Med Genet. 2009 Jun 6;10:51. doi: 10.1186/1471-2350-10-51.

PubMed [citation]

PMID:: 19500388
PMCID:: PMC2702372

Clinical and genetic aspects of hypophosphatasia in Japanese patients.

Taketani T, Onigata K, Kobayashi H, Mushimoto Y, Fukuda S, Yamaguchi S.

Arch Dis Child. 2014 Mar;99(3):211-5. doi: 10.1136/archdischild-2013-305037. Epub 2013 Nov 25.

PubMed [citation]

PMID:: 24276437

See all PubMed Citations (12)

Details of each submission

From Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota, SCV001981524.1

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

#	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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819339.1

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

Description

Variant summary: ALPL c.550C>T (p.Arg184Trp) results in a non-conservative amino acid change located in the active site domain (Zurutuza_1999) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251120 control chromosomes. c.550C>T has been reported in the literature in both heterozygous as well as biallelic compound heterozygous genotypes in multiple individuals affected with Perinatal/Odonto/Perinatal benign and adult forms of Hypophosphatasia ((example, PMID: 30049651, 32160374, 19500388, 33814268, 31600233, 19232125, 33549410, 26432670, 24276437, 25731960, 10222035). These data indicate that the variant is very likely to be associated with disease. At least two publications report consistent experimental evidence evaluating an impact on protein function (example, 19500388, 32160374). The most pronounced variant effect results in <1% of normal tissue-nonspecific alkaline phosphatase (TNSALP) activity in-vitro and a dominant negative effect in a heterozygous genotype. The dominant mutations are considered severe alleles that inhibit the normal monomer when both the normal and the mutated protein form a dimer. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=1; P/LP, n=5). Based on the evidence outlined above, the variant was 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 JKU Lab, Dept of Paediatrics, Johannes Kepler University, SCV004174856.1

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

Description

A case was submitted to the ALPL gene variant database for reclassification with 4 mutations c.[550C>T];[62-29G>A];[455G>A];[330T>C]. c.550C>T has conflicting interpretations of pathogenicity Pathogenic(6); Likely pathogenic(3); Uncertain significance(1) in ClinVar. c.455G>A is Benign/Likely benign in ClinVar c.62-29G>A is Likely benign in ClinVar. c.330T>C is benign.

Description

GnomAD frequencies ALL:0.0014% - AMR:0.0028% - NFE:0.0023%. Further information on the ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/

#	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		1	not provided	not provided	not provided

Last Updated: May 19, 2024

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