ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.667C>T (p.Arg223Trp)

gnomAD frequency: 0.00002  dbSNP: rs766076920
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000169383 SCV000220773 likely pathogenic Infantile hypophosphatasia 2014-10-09 criteria provided, single submitter literature only
Invitae RCV001208323 SCV001379703 pathogenic not provided 2024-01-10 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 223 of the ALPL protein (p.Arg223Trp). This variant is present in population databases (rs766076920, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia (PMID: 11760847, 23454488, 24100244). This variant is also known as p.Arg206Trp. ClinVar contains an entry for this variant (Variation ID: 189001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALPL protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects ALPL function (PMID: 11760847, 23454488). This variant disrupts the p.Arg223 amino acid residue in ALPL. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11855933, 15694177, 23509830, 24100244). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
DASA RCV001831990 SCV002107089 pathogenic Hypophosphatasia 2022-03-05 criteria provided, single submitter clinical testing Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product (PMID: 23454488) - PS3_moderate.The c.667C>T;p.(Arg223Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 189001; PMID: 24100244; PMID: 23454488; PMID: 20383509) - PS4. The variant is located in a mutational hot spot and/or critical and well-established functional domain (Alk-phosphatase) - PM1. The variant is present at low allele frequencies population databases (rs766076920 – gnomAD 0.0001061%; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg223Trp) was detected in trans with a pathogenic variant (PMID: 24100244; PMID: 23454488; PMID: 20383509) - PM3. Pathogenic missense variant in this residue have been reported (ClinVar ID: 381586) - PM5. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. The variant was identified in an individual with a highly specific phenotype for the condition -PP4. In summary, the currently available evidence indicates that the variant is pathogenic.
Baylor Genetics RCV003468842 SCV004193283 pathogenic Adult hypophosphatasia 2023-02-08 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001831990 SCV004241599 pathogenic Hypophosphatasia 2023-12-22 criteria provided, single submitter clinical testing Variant summary: ALPL c.667C>T (p.Arg223Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251478 control chromosomes (gnomAD). c.667C>T (also known as R206W) has been reported in the literature in multiple bi-allelic individuals affected with Hypophosphatasia (example: Mornet_1998, Brun-Heath_2005, Collman_2009, Orimo_2009, Hofmann_2013, McKiernan_2017, DelAngel_2020), however some of these individual had variants classified as VUS or likely benign in trans (Orimo_2009, Brun-Heath_2005). Multiple publications have reported experimental evidence evaluating an impact on protein function. All of these studies have shown variant effect results in <10% of normal activity (example: Hofmann_2013, Orimo_2009, Brun-Heath_2005). The following publications have been ascertained in the context of this evaluation (PMID: 23454488, 11760847, 18769927, 9781036, 28401263, 15694177, 32160374). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Natera, Inc. RCV001831990 SCV002094067 pathogenic Hypophosphatasia 2021-05-18 no assertion criteria provided clinical testing

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