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NM_000478.6(ALPL):c.532T>C (p.Tyr178His) AND Hypophosphatasia

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 1, 2024
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:
RCV004526122.2

Allele description [Variation Report for NM_000478.6(ALPL):c.532T>C (p.Tyr178His)]

NM_000478.6(ALPL):c.532T>C (p.Tyr178His)

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.532T>C (p.Tyr178His)
HGVS:
  • NC_000001.11:g.21564100T>C
  • NG_008940.1:g.59736T>C
  • NM_000478.6:c.532T>CMANE SELECT
  • NM_001127501.4:c.367T>C
  • NM_001177520.3:c.301T>C
  • NM_001369803.2:c.532T>C
  • NM_001369804.2:c.532T>C
  • NM_001369805.2:c.532T>C
  • NP_000469.3:p.Tyr178His
  • NP_001120973.2:p.Tyr123His
  • NP_001170991.1:p.Tyr101His
  • NP_001356732.1:p.Tyr178His
  • NP_001356733.1:p.Tyr178His
  • NP_001356734.1:p.Tyr178His
  • NC_000001.10:g.21890593T>C
  • NM_000478.4:c.532T>C
Protein change:
Y101H
Links:
dbSNP: rs1215600806
NCBI 1000 Genomes Browser:
rs1215600806
Molecular consequence:
  • NM_000478.6:c.532T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127501.4:c.367T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177520.3:c.301T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369803.2:c.532T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369804.2:c.532T>C - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369805.2:c.532T>C - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

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

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV005040486Women's Health and Genetics/Laboratory Corporation of America, LabCorp
criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)
Pathogenic
(Mar 1, 2024)
germlineclinical testing

PubMed (3)
[See all records that cite these PMIDs]

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Discordant fetal phenotype of hypophosphatasia in two siblings.

Ikenoue S, Miyakoshi K, Ishii T, Sato Y, Otani T, Akiba Y, Kasuga Y, Ochiai D, Matsumoto T, Ichihashi Y, Matsuzaki Y, Tachikawa K, Michigami T, Nishimura G, Ikeda K, Hasegawa T, Tanaka M.

Am J Med Genet A. 2018 Jan;176(1):171-174. doi: 10.1002/ajmg.a.38531. Epub 2017 Nov 21.

PubMed [citation]
PMID:
29160033

A compound heterozygous ALPL variant in a patient with dystonia-parkinsonism and hypointensity in basal ganglia: A case report.

Li XY, Wan XH, Chen L, Guo WH, Wang L.

Parkinsonism Relat Disord. 2020 Sep;78:184-185. doi: 10.1016/j.parkreldis.2020.07.027. Epub 2020 Aug 12. No abstract available.

PubMed [citation]
PMID:
32956941
See all PubMed Citations (3)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV005040486.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (3)

Description

Variant summary: ALPL c.532T>C (p.Tyr178His) results in a conservative amino acid change in the encoded protein sequence. Four 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 251150 control chromosomes (gnomAD). c.532T>C has been reported in the literature in individuals affected with Hypophosphatasia who were compound heterozygous with other (likely) pathogenic variants (Ikenoue_2018, Uday_2019, Li_2020). These data indicate that the variant is likely to be associated with disease. Publications reports experimental evidence evaluating an impact on protein function, finding that the variant eliminates ALPL activity (Ikenoue_2018, Uday_2019). The following publications have been ascertained in the context of this evaluation (PMID: 29160033, 31146036, 32956941). ClinVar contains an entry for this variant (Variation ID: 1076160). Based on the evidence outlined above, the variant was classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Jul 7, 2024