ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.346G>A (p.Ala116Thr) (rs121918013)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169426 SCV000220835 likely pathogenic Infantile hypophosphatasia 2014-10-24 criteria provided, single submitter literature only
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224118 SCV000280959 pathogenic not provided 2016-01-12 criteria provided, single submitter clinical testing
GeneDx RCV000224118 SCV000322323 pathogenic not provided 2018-05-30 criteria provided, single submitter clinical testing The A116T variant in the ALPL gene has been reported previously (as A99T due to the use of alternative nomenclature) in association with autosomal dominant hypophosphatasia (Hu et al., 2000; Saglam et al., 2017). Functional studies demonstrate that the A116T variant results in decreased alkaline phosphatase activity via a dominant-negative effect (Lia-Baldini et al., 2001; Foster et al., 2015). The A116T variant is not observed in large population cohorts (Lek et al., 2016). The A116T variant is a non-conservative amino acid substitution which occurs at a position that is conserved across species. We interpret A116T as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000590781 SCV000696799 pathogenic Hypophosphatasia 2016-09-26 criteria provided, single submitter clinical testing Variant summary: The ALPL c.346G>A (p.Ala116Thr) variant, alternatively also known as A99T, involves the alteration of a conserved nucleotide. The amino acid change is located in alpha helix of the protein which runs from the active site to the surface of the molecule near the homodimer interface (InterPro, Herasse_2003). 3/3 in silico tools predict a damaging outcome for this variant. This variant is absent in 120682 control chromosomes from ExAC. In heterozygous state, the variant is reported to cause dominant HPP; the patients carrying the variant in heterozygous state show very moderate clinical symptoms corresponding to adult or odontohypophosphatasia (Hu_2001, Herasse_2003). In compound heterozygous state with other pathogenic or likely pathogenic variant under recessive inheritance pattern, the variant causes severe childhood/neonatal HPP (Taillandier _2001, Whyte_2015). In vitro studies show that this variant leads to severely reduced alkaline phosphatase activity, also showing a weak dominant negative effect when co-expressed with the wild-type enzyme (Lia-Baldini_2001, Fauvert_2009, Ishida_2011) with consistent finding by an in vivo mouse model study (Foster_2011). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as likely pathogenic. Taken together, this variant is classified as Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000224118 SCV000706403 pathogenic not provided 2017-03-02 criteria provided, single submitter clinical testing
Invitae RCV000224118 SCV000939644 pathogenic not provided 2018-09-24 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 116 of the ALPL protein (p.Ala116Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in combination with another ALPL variant in individuals affected with severe hypophosphatasias (PMID: 10679946, 11438998, 25731960), and has been shown to segregate with autosomal dominant hypophosphatasia in a heterozygous state in several families (PMID: 10872988, 12920074). This variant is also known as A94T and A99T in the literature. ClinVar contains an entry for this variant (Variation ID: 13677). Experimental studies have shown that this missense change causes reduced enzume activity and exhibits a weak dominant negative effect on protein function (PMID: 21168482, 25716980). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000014668 SCV000034923 pathogenic Childhood hypophosphatasia 2003-08-01 no assertion criteria provided literature only
OMIM RCV000014669 SCV000034924 pathogenic Adult hypophosphatasia 2003-08-01 no assertion criteria provided literature only
OMIM RCV000014670 SCV000034925 pathogenic Odontohypophosphatasia 2003-08-01 no assertion criteria provided literature only

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