ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.303C>A (p.Tyr101Ter)

gnomAD frequency: 0.00002  dbSNP: rs746273959
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001389868 SCV001591390 pathogenic not provided 2024-12-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr101*) in the ALPL gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALPL are known to be pathogenic (PMID: 3174660, 10679946, 32973344, 33814268). This variant is present in population databases (rs746273959, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with ALPL-related conditions. ClinVar contains an entry for this variant (Variation ID: 1076087). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV001449738 SCV001653009 likely pathogenic Infantile hypophosphatasia 2020-06-11 criteria provided, single submitter clinical testing The p.Tyr101X variant in ALPL has been reported in the heterozygous state in 1 individual with osteoporosis and low circulating concentrations of alkaline phosphatase (AP; Alonso 2019 PMID: 31793067). It has also been identified in 0.004% (4/113178) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This nonsense variant leads to a premature termination codon at position 101, which is predicted to lead to a truncated or absent protein. While hypophosphatasia can be inherited in an autosomal dominant or autosomal recessive manner, loss-of-function variants like the p.Tyr101X variant are primarily associated with recessive inheritance. Although individuals harboring heterozygous loss-of-function variants may have low serum AP levels, they are typically asymptomatic. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive hypophosphatasia. ACMG/AMP Criteria applied: PVS1, PM2.
Baylor Genetics RCV003469765 SCV004193039 pathogenic Adult hypophosphatasia 2023-05-03 criteria provided, single submitter clinical testing

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