NM_000478.6(ALPL):c.920C>T (p.Pro307Leu) AND Hypophosphatasia

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Dec 11, 2022
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:: RCV002509351.1

Allele description [Variation Report for NM_000478.6(ALPL):c.920C>T (p.Pro307Leu)]

NM_000478.6(ALPL):c.920C>T (p.Pro307Leu)

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.920C>T (p.Pro307Leu)

HGVS:

NC_000001.11:g.21573722C>T
NG_008940.1:g.69358C>T
NM_000478.6:c.920C>TMANE SELECT
NM_001127501.4:c.755C>T
NM_001177520.3:c.689C>T
NM_001369803.2:c.920C>T
NM_001369804.2:c.920C>T
NM_001369805.2:c.920C>T
NP_000469.3:p.Pro307Leu
NP_001120973.2:p.Pro252Leu
NP_001170991.1:p.Pro230Leu
NP_001356732.1:p.Pro307Leu
NP_001356733.1:p.Pro307Leu
NP_001356734.1:p.Pro307Leu
NC_000001.10:g.21900215C>T
NM_000478.5:c.920C>T

Protein change:

P230L

Links:

dbSNP: rs768555495

NCBI 1000 Genomes Browser:

rs768555495

Molecular consequence:

NM_000478.6:c.920C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.755C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.689C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.920C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.920C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.920C>T - missense variant - [Sequence Ontology: SO:0001583]

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
SCV002819430	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Dec 11, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID] Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002819430

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Pathogenic
(Dec 11, 2022)

germline

clinical testing

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

Citation Link

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

Large-scale in vitro functional testing and novel variant scoring via protein modeling provide insights into alkaline phosphatase activity in hypophosphatasia.

Del Angel G, Reynders J, Negron C, Steinbrecher T, Mornet E.

Hum Mutat. 2020 Jul;41(7):1250-1262. doi: 10.1002/humu.24010. Epub 2020 Mar 18.

PubMed [citation]

PMID:: 32160374
PMCID:: PMC7317754

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002819430.1

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

Description

Variant summary: ALPL c.920C>T (p.Pro307Leu) results in a non-conservative amino acid change located in the Calcium site domain (del Angel_2020) 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 8e-06 in 251168 control chromosomes. c.920C>T has been reported in the literature in multiple individuals affected with Hypophosphatasia (Del Angel_2020). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Del Angel_2020). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. One laboratory classified the variant as pathogenic/likely pathogenic and one laboratory classified the variant as uncertain significance (presumably out dated classification). 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

Last Updated: Sep 29, 2024

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