Submissions for variant NM_000478.6(ALPL):c.550C>T (p.Arg184Trp)

gnomAD frequency: 0.00001  dbSNP: rs763159520

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000623730	SCV000741935	pathogenic	Inborn genetic diseases	2024-04-15	criteria provided, single submitter	clinical testing	The c.550C>T (p.R184W) alteration is located in exon 6 (coding exon 5) of the ALPL gene. This alteration results from a C to T substitution at nucleotide position 550, causing the arginine (R) at amino acid position 184 to be replaced by a tryptophan (W). This variant has been identified in conjunction with other ALPLvariant(s) in individuals with features consistent with ALPL-related hypophosphatasia (Mornet, 1993; Reibel, 2009; Rockman-Greenberg, 2022; Yazici, 2022). In multiple assays testing ALPL function, this variant showed a significant decrease in alkaline phosphatase activity; however, in assays testing a dominant negative effect, this variant showed varying results (Lia-Baldini, 2001; Fauvert, 2009; Michigami, 2020; Del Angel, 2020). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (4/282484) total alleles studied. The highest observed frequency was 0.003% (1/35408) of Latino alleles. This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of the ALPL c.550C>T (p.R184W) alteration is pathogenic for autosomal dominant and autosomal recessive ALPL-related hypophosphatasia (loss of function mechanism of disease); however, its clinical significance for autosomal dominant ALPL-related hypophosphatasia (dominant negative mechanism of disease) is uncertain.
Counsyl	RCV000674297	SCV000799608	likely pathogenic	Infantile hypophosphatasia	2018-05-03	criteria provided, single submitter	clinical testing
Invitae	RCV001046115	SCV001210003	pathogenic	not provided	2024-01-12	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 184 of the ALPL protein (p.Arg184Trp). This variant is present in population databases (rs763159520, gnomAD 0.003%). This missense change has been observed in individual(s) with hypophosphatasia and thus appears to be associated with both dominant and recessive ALPL-related disease (PMID: 9781036, 10332035, 11479741, 19232125, 19500388, 24276437, 25731960, 26432670). It has also been observed to segregate with disease in related individuals. This variant is also known as p.Arg167Trp. ClinVar contains an entry for this variant (Variation ID: 521379). 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: 11479741, 19500388). For these reasons, this variant has been classified as Pathogenic.
Blueprint Genetics	RCV001046115	SCV001832337	pathogenic	not provided	2019-11-30	criteria provided, single submitter	clinical testing
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV001730702	SCV001981524	pathogenic	Hypophosphatasia	2021-09-15	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002279446	SCV002564794	likely pathogenic	Osteogenesis imperfecta	2020-09-04	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001046115	SCV002817223	likely pathogenic	not provided	2021-02-11	criteria provided, single submitter	clinical testing	This variant has been identified in multiple individuals associated with autosomal dominant and recessive ALPL-related disorders (PMID: 25731960, 32160374, 31600233, 19232125, 19500388). Assessment of experimental evidence suggests this variant may have a dominant-negative effect and could result in abnormal protein function (PMID: 19500388, 31707452). The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001730702	SCV002819339	pathogenic	Hypophosphatasia	2022-12-08	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.550C>T (p.Arg184Trp) results in a non-conservative amino acid change located in the active site domain (Zurutuza_1999) of 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 1.2e-05 in 251120 control chromosomes. c.550C>T has been reported in the literature in both heterozygous as well as biallelic compound heterozygous genotypes in multiple individuals affected with Perinatal/Odonto/Perinatal benign and adult forms of Hypophosphatasia ((example, PMID: 30049651, 32160374, 19500388, 33814268, 31600233, 19232125, 33549410, 26432670, 24276437, 25731960, 10222035). These data indicate that the variant is very likely to be associated with disease. At least two publications report consistent experimental evidence evaluating an impact on protein function (example, 19500388, 32160374). The most pronounced variant effect results in <1% of normal tissue-nonspecific alkaline phosphatase (TNSALP) activity in-vitro and a dominant negative effect in a heterozygous genotype. The dominant mutations are considered severe alleles that inhibit the normal monomer when both the normal and the mutated protein form a dimer. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=1; P/LP, n=5). Based on the evidence outlined above, the variant was classified as pathogenic.
Revvity Omics, Revvity	RCV001046115	SCV003817229	pathogenic	not provided	2022-08-03	criteria provided, single submitter	clinical testing
GeneDx	RCV001046115	SCV003845631	pathogenic	not provided	2023-03-17	criteria provided, single submitter	clinical testing	Published functional studies show significantly reduced activity compared to wildtype and demonstrate a dominant-negative effect (Fauvert et al., 2009; Del Angel et al., 2020); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25731960, 23791648, 26432670, 19232125, 26219717, 9781036, 19500388, 11479741, 31600233, 29236161, 31707452, 35068125, 33349304, 36553293, 33814268, 36097602, 30049651, 24276437, 10332035, 32160374, 33549410)
JKU Lab, Dept of Paediatrics, Johannes Kepler University	RCV001730702	SCV004174856	pathogenic	Hypophosphatasia	2022-03-04	criteria provided, single submitter	clinical testing	GnomAD frequencies ALL:0.0014% - AMR:0.0028% - NFE:0.0023%. Further information on the ACMG criteria applied can be looked up in the ALPL gene variant database. https://alplmutationdatabase.jku.at/
Baylor Genetics	RCV003465357	SCV004194407	pathogenic	Adult hypophosphatasia	2024-01-20	criteria provided, single submitter	clinical testing