Submissions for variant NM_000478.6(ALPL):c.182-2A>G

dbSNP: rs2148152217

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001390683	SCV001592484	pathogenic	not provided	2020-04-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 3 of the ALPL gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). Disruption of this splice site has been observed in individual(s) with hypophosphatasia (PMID: 25731960). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALPL are known to be pathogenic (PMID: 3174660, 10679946, 19500388). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies.
JKU Lab, Dept of Paediatrics, Johannes Kepler University	RCV003447597	SCV004174857	likely pathogenic	Hypophosphatasia	2022-04-19	criteria provided, single submitter	clinical testing	Absent from GnomAD. Splice acceptor of exon 4. Further information on ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/.