ClinVar Miner

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

gnomAD frequency: 0.00001  dbSNP: rs1057517391
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana RCV001195741 SCV001366161 likely pathogenic Adult hypophosphatasia 2020-03-14 criteria provided, single submitter clinical testing This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2.
Labcorp Genetics (formerly Invitae), Labcorp RCV001387323 SCV001587926 pathogenic not provided 2023-08-14 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in intron 9 of the ALPL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site 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, 32973344, 33814268). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with hypophosphatasia (PMID: 10679946, 15694177, 20924064, 23791648). ClinVar contains an entry for this variant (Variation ID: 930227). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001779133 SCV002015047 pathogenic Hypophosphatasia 2021-10-24 criteria provided, single submitter clinical testing Variant summary: ALPL c.997+2T>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 250984 control chromosomes. c.997+2T>A has been widely reported in the literature as a compound heterozygous genotype in individuals affected with Hypophosphatasia (example, Taillandier_2000, Del Angel_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Ambry Genetics RCV002560208 SCV003722509 pathogenic Inborn genetic diseases 2022-03-04 criteria provided, single submitter clinical testing 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.
Baylor Genetics RCV001195741 SCV004193061 pathogenic Adult hypophosphatasia 2024-02-20 criteria provided, single submitter clinical testing
Natera, Inc. RCV001779133 SCV002094082 pathogenic Hypophosphatasia 2020-12-22 no assertion criteria provided clinical testing

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