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NM_000478.6(ALPL):c.997+2T>A AND Inborn genetic diseases

Germline classification:
Pathogenic (1 submission)
Last evaluated:
Mar 4, 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:
RCV002560208.1

Allele description [Variation Report for NM_000478.6(ALPL):c.997+2T>A]

NM_000478.6(ALPL):c.997+2T>A

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.997+2T>A
HGVS:
  • NC_000001.11:g.21573801T>A
  • NG_008940.1:g.69437T>A
  • NG_008940.2:g.69819T>A
  • NM_000478.6:c.997+2T>AMANE SELECT
  • NM_001127501.4:c.832+2T>A
  • NM_001177520.3:c.766+2T>A
  • NM_001369803.2:c.997+2T>A
  • NM_001369804.2:c.997+2T>A
  • NM_001369805.2:c.997+2T>A
  • NC_000001.10:g.21900294T>A
  • NM_000478.4:c.997+2T>A
  • NM_000478.5:c.997+2T>A
Links:
dbSNP: rs1057517391
NCBI 1000 Genomes Browser:
rs1057517391
Molecular consequence:
  • NM_000478.6:c.997+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001127501.4:c.832+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001177520.3:c.766+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001369803.2:c.997+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001369804.2:c.997+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
  • NM_001369805.2:c.997+2T>A - splice donor variant - [Sequence Ontology: SO:0001575]
Observations:
1

Condition(s)

Name:
Inborn genetic diseases
Identifiers:
MeSH: D030342; MedGen: C0950123

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003722509Ambry Genetics
criteria provided, single submitter

(Ambry General Variant Classification Scheme_2022)		Pathogenic
(Mar 4, 2022) 		germlineclinical testing

PubMed (4)
[See all records that cite these PMIDs]

Citation Link

Help

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknown1not providednot provided1not providedclinical testing

Citations

PubMed

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

Fifteen new mutations (-195C>T, L-12X, 298-2A>G, T117N, A159T, R229S, 997+2T>A, E274X, A331T, H364R, D389G, 1256delC, R433H, N461I, C472S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene in patients with hypophosphatasia.

Taillandier A, Cozien E, Muller F, Merrien Y, Bonnin E, Fribourg C, Simon-Bouy B, Serre JL, Bieth E, Brenner R, Cordier MP, De Bie S, Fellmann F, Freisinger P, Hesse V, Hennekam RC, Josifova D, Kerzin-Storrar L, Leporrier N, Zabot MT, Mornet E.

Hum Mutat. 2000 Mar;15(3):293.

PubMed [citation]
PMID:
10679946
See all PubMed Citations (4)

Details of each submission

From Ambry Genetics, SCV003722509.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not provided1not providednot providedclinical testing PubMed (4)

Description

The c.997+2T>A intronic variant results from a T to A substitution two nucleotides after exon 9 (coding exon 8) of the ALPL gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the available evidence, the c.997+2T>A alteration is pathogenic for autosomal recessive hypophosphatasia; however, its clinical significance for autosomal dominant hypophosphatasia is unclear. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the homozygous and compound heterozygous state in individuals with hypophosphatasia (Taillandier, 2000; Brun-Heath, 2005). Other alterations impacting the same donor site (c.997+1G>T and c.997+2T>G) have been detected in individuals with hypophosphatasia (Brun-Heath, 2005; Simon-Bouy, 2008; Liu, 2010). In silico splice site analysis predicts that this alteration will weaken the native splice donor site. Based on the available evidence, this alteration is classified as pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknown1not providednot provided1not providednot providednot provided

Last Updated: Feb 20, 2024