ClinVar Miner

Submissions for variant NM_000478.6(ALPL):c.1250A>G (p.Asn417Ser) (rs121918014)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000710510 SCV000332907 likely pathogenic not provided 2015-07-16 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000710510 SCV000840747 likely pathogenic not provided 2018-07-17 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001194283 SCV001363683 pathogenic Hypophosphatasia 2019-08-05 criteria provided, single submitter clinical testing Variant summary: ALPL c.1250A>G (p.Asn417Ser) results in a conservative amino acid change located in the Crown domain (Simon-Bouy_2008) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251442 control chromosomes (gnomAD). c.1250A>G has been reported in the literature as a single heterozygous variant (i.e. no other variants detected) in multiple individuals with features of mild HPP (odontohypophosphatasia, adult and childhood hypophosphatasia) but also in at least 2 parents that were carriers of the variant without any reported symptoms (Fauvert_2009, Reibel_2009, Whyte_2015). It has also been reported in compound heterozygous state with other pathogenic variants in patients affected with severe perinatal or severe childhood hypophosphatasia (Sergi_2001, Whyte_2015). These data indicate that the variant is very likely to be associated with disease. Using a cell system Fauvert et al reported that this variant has a dominant negative effect (Fauvert_2009) on wild-type enzymatic activity. In addition, Sultana et al performed several functional experiments using an in vitro system and concluded that a complete loss of ALP enzymatic activity resulting from the disruption of its functional dimer structure may represent the molecular basis of HPP associated with ALPL N417S (Sultana_2013). Three ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000710510 SCV001405222 pathogenic not provided 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 417 of the ALPL protein (p.Asn417Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs121918014, ExAC 0.009%). This variant has been observed to segregate with hypophosphatasia in a family (PMID: 25731960) and has also been observed in individuals with hypophosphatasia (PMID: 11745997, 25731960, 27998428). This variant is also known as p.Asn400Ser in the literature. ClinVar contains an entry for this variant (Variation ID: 13679). This variant has been reported to affect ALPL protein function (PMID: 19500388; 23688511). For these reasons, this allele has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center RCV001253058 SCV001428580 pathogenic Adult hypophosphatasia 2017-09-28 criteria provided, single submitter clinical testing
Johns Hopkins Genomics, Johns Hopkins University RCV001253058 SCV001711955 pathogenic Adult hypophosphatasia 2021-05-25 criteria provided, single submitter clinical testing
OMIM RCV000169778 SCV000034927 pathogenic Hypophosphatasia, perinatal lethal 2001-10-15 no assertion criteria provided literature only
Counsyl RCV000014672 SCV000221154 pathogenic Infantile hypophosphatasia 2018-10-03 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.