NM_000478.6(ALPL):c.178G>C (p.Asp60His) AND not specified

Germline classification:: Uncertain significance (1 submission)
Last evaluated:: Feb 14, 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:: RCV001192372.2

Allele description [Variation Report for NM_000478.6(ALPL):c.178G>C (p.Asp60His)]

NM_000478.6(ALPL):c.178G>C (p.Asp60His)

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.178G>C (p.Asp60His)

HGVS:

NC_000001.11:g.21560742G>C
NG_008940.1:g.56378G>C
NM_000478.6:c.178G>CMANE SELECT
NM_001127501.4:c.13G>C
NM_001177520.3:c.63G>C
NM_001369803.2:c.178G>C
NM_001369804.2:c.178G>C
NM_001369805.2:c.178G>C
NP_000469.3:p.Asp60His
NP_001120973.2:p.Asp5His
NP_001170991.1:p.Glu21Asp
NP_001356732.1:p.Asp60His
NP_001356733.1:p.Asp60His
NP_001356734.1:p.Asp60His
NC_000001.10:g.21887235G>C
NM_000478.4:c.178G>C
NM_000478.5:c.178G>C

Protein change:

D5H

Links:

dbSNP: rs1644472852

NCBI 1000 Genomes Browser:

rs1644472852

Molecular consequence:

NM_000478.6:c.178G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001127501.4:c.13G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001177520.3:c.63G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001369803.2:c.178G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001369804.2:c.178G>C - missense variant - [Sequence Ontology: SO:0001583]
NM_001369805.2:c.178G>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: AllHighlyPenetrant
Identifiers:: MedGen: CN169374

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rasa1a RAS p21 protein activator (GTPase activating protein) 1a [Danio rerio]
rasa1a RAS p21 protein activator (GTPase activating protein) 1a [Danio rerio]
Gene ID:100002155

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001360431	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Uncertain significance (Feb 14, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 28401263, 32879991 Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV001360431

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Uncertain significance
(Feb 14, 2022)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

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

Mutational and biochemical findings in adults with persistent hypophosphatasemia.

McKiernan FE, Dong J, Berg RL, Scotty E, Mundt P, Larson L, Rai I.

Osteoporos Int. 2017 Aug;28(8):2343-2348. doi: 10.1007/s00198-017-4035-y. Epub 2017 Apr 12.

PubMed [citation]

PMID:: 28401263

Bone mineral density and fracture risk in adult patients with hypophosphatasia.

Genest F, Claußen L, Rak D, Seefried L.

Osteoporos Int. 2021 Feb;32(2):377-385. doi: 10.1007/s00198-020-05612-9. Epub 2020 Sep 2.

PubMed [citation]

PMID:: 32879991
PMCID:: PMC7838076

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV001360431.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: ALPL c.178G>C (p.Asp60His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251250 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.178G>C has been reported in the literature with hypophosphataemia without evidence for causality (Examples: McKiernan_2017 and Genest_2021). These reports do not provide unequivocal conclusions about association of the variant with Hypophosphatasia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance.

#	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: Feb 20, 2024

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