ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.400_401delinsCA (p.Thr134His) (rs786204530)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169231 SCV000220500 likely pathogenic Infantile hypophosphatasia 2014-07-10 criteria provided, single submitter literature only
Fulgent Genetics,Fulgent Genetics RCV000763298 SCV000893963 pathogenic Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000350796 SCV000329063 pathogenic not provided 2018-07-13 criteria provided, single submitter clinical testing The c.400_401delACinsCA variant in the ALPL gene has been reported previously in association with hypophophatasia when in trans with another disease causing variant in ALPL (Mumm et al., 2002; Peach et al., 2007; Simon-Bouy et al., 2008; Whyte et al., 2009; Cundy et al., 2015). The c.400_401delACinsCA variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The c.400_401delACinsCA variant causes an in-frame deletion of two nucleotides, resulting in a substitution of Threonine for Histidine at codon 134, denoted p.Thr134His (T134H). This substitution results in a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is not conserved. In vitro functional studies of COS7 cells expressing T134H-ALPL demonstrated almost no enzyme activity (Cundy et al., 2015). Missense variants in nearby residues (G129R, A132V, A132T, T134N, R136C, R136H, R136L, R136P) have been reported in the Human Gene Mutation Database in association with hypophosphatasia (Stenson et al., 2014), supporting the functional importance of this region of the protein. We interpret c.400_401delACinsCA as a pathogenic variant.
GenomeConnect, ClinGen RCV000845007 SCV000986837 not provided Hypophosphatemia no assertion provided phenotyping only Variant interpretted as pathogenic and reported on 07/24/2018 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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