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NM_000478.6(ALPL):c.1231A>G (p.Thr411Ala) AND not provided

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Jan 14, 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:
RCV001953835.6

Allele description [Variation Report for NM_000478.6(ALPL):c.1231A>G (p.Thr411Ala)]

NM_000478.6(ALPL):c.1231A>G (p.Thr411Ala)

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.1231A>G (p.Thr411Ala)
HGVS:
  • NC_000001.11:g.21576563A>G
  • NG_008940.1:g.72199A>G
  • NM_000478.6:c.1231A>GMANE SELECT
  • NM_001127501.4:c.1066A>G
  • NM_001177520.3:c.1000A>G
  • NM_001369803.2:c.1231A>G
  • NM_001369804.2:c.1231A>G
  • NM_001369805.2:c.1231A>G
  • NP_000469.3:p.Thr411Ala
  • NP_001120973.2:p.Thr356Ala
  • NP_001170991.1:p.Thr334Ala
  • NP_001356732.1:p.Thr411Ala
  • NP_001356733.1:p.Thr411Ala
  • NP_001356734.1:p.Thr411Ala
  • NC_000001.10:g.21903056A>G
Protein change:
T334A
Links:
dbSNP: rs2148192403
NCBI 1000 Genomes Browser:
rs2148192403
Molecular consequence:
  • NM_000478.6:c.1231A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001127501.4:c.1066A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001177520.3:c.1000A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369803.2:c.1231A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369804.2:c.1231A>G - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001369805.2:c.1231A>G - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:
none provided
Identifiers:
MedGen: C3661900

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV002246412Labcorp Genetics (formerly Invitae), Labcorp
criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))		Pathogenic
(Jan 14, 2024) 		germlineclinical testing

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

Help

Summary from all submissions

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

Citations

PubMed

Enzyme-replacement therapy in life-threatening hypophosphatasia.

Whyte MP, Greenberg CR, Salman NJ, Bober MB, McAlister WH, Wenkert D, Van Sickle BJ, Simmons JH, Edgar TS, Bauer ML, Hamdan MA, Bishop N, Lutz RE, McGinn M, Craig S, Moore JN, Taylor JW, Cleveland RH, Cranley WR, Lim R, Thacher TD, Mayhew JE, et al.

N Engl J Med. 2012 Mar 8;366(10):904-13. doi: 10.1056/NEJMoa1106173.

PubMed [citation]
PMID:
22397652

Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations.

Brun-Heath I, Taillandier A, Serre JL, Mornet E.

Mol Genet Metab. 2005 Mar;84(3):273-7. Epub 2004 Dec 19.

PubMed [citation]
PMID:
15694177
See all PubMed Citations (3)

Details of each submission

From Labcorp Genetics (formerly Invitae), Labcorp, SCV002246412.3

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

Description

This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 411 of the ALPL protein (p.Thr411Ala). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with hypophosphatasia (PMID: 15694177, 22397652; Invitae). This variant is also known as p.Thr394Ala. ClinVar contains an entry for this variant (Variation ID: 1457576). 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) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 15694177). For these reasons, this variant has been classified as Pathogenic.

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

Last Updated: Sep 29, 2024