Submissions for variant NM_000478.6(ALPL):c.1542G>T (p.Ala514=)

gnomAD frequency: 0.01113  dbSNP: rs3200256

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
PreventionGenetics, part of Exact Sciences	RCV000250762	SCV000304433	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000297950	SCV000354318	benign	Hypophosphatasia	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Athena Diagnostics Inc	RCV000710512	SCV000840750	benign	not provided	2018-01-11	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000250762	SCV000918420	benign	not specified	2018-04-13	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1542G>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0089 in 260566 control chromosomes, predominantly within the Finnish subpopulation at a frequency of 0.018, including 5 homozygotes (in the gnomAD database). The observed variant frequency within Finnish control individuals in the gnomAD database is approximately 5 fold of the estimated maximal expected allele frequency for a pathogenic variant in ALPL causing Hypophosphatasia phenotype (0.0035), strongly suggesting that the variant is a benign polymorphism. c.1542G>T has been reported in the literature in individuals affected with Hypophosphatasia but it was also found in normal controls (Nielson 2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae	RCV000710512	SCV001109930	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000710512	SCV001472411	benign	not provided	2023-11-29	criteria provided, single submitter	clinical testing
GeneDx	RCV000710512	SCV001813091	likely benign	not provided	2021-10-26	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002277610	SCV002565154	benign	Osteogenesis imperfecta	2022-03-15	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000710512	SCV004009745	benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	ALPL: BP4, BP7, BS1, BS2
Natera, Inc.	RCV000297950	SCV001459888	benign	Hypophosphatasia	2020-09-16	no assertion criteria provided	clinical testing