Submissions for variant NM_000478.6(ALPL):c.1559del (p.Leu520fs)

gnomAD frequency: 0.00001  dbSNP: rs387906525

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000346130	SCV000331660	pathogenic	not provided	2014-10-14	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000014665	SCV001194091	pathogenic	Infantile hypophosphatasia	2019-12-26	criteria provided, single submitter	clinical testing	NM_000478.4(ALPL):c.1559delT(L520Rfs*86) is classified as pathogenic in the context of hypophosphatasia. Sources cited for classification include the following: PMID 23926372, 9452105, 15660230, 18455459, 15660230 and 15794757. Classification of NM_000478.4(ALPL):c.1559delT(L520Rfs*86) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000207209	SCV001338324	pathogenic	Hypophosphatasia	2020-02-24	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.1559delT (p.Leu520ArgfsX86) causes a frameshift which results in an extension of the protein. The variant allele was found at a frequency of 8.7e-06 in 230820 control chromosomes (genomAD). In Japanese HPP, this variant is the most frequent mutation (Komaru_2005, Michigami_2019, Okawa_2019). c.1559delT has been reported in the literature in compound heterozygous and homozygous individuals affected with Hypophosphatasia (Okawa_2019, Koyama_2019). These data indicate that the variant is very likely to be associated with disease. At least one functional study reports this variant effect results in decreasing normal activity (Komaru_2005). One ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000346130	SCV001385930	pathogenic	not provided	2024-08-28	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Leu520Argfs*86) in the ALPL gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 5 amino acid(s) of the ALPL protein. This variant is present in population databases (rs387906525, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with hypophosphatasia (PMID: 7833929, 9814472, 15660230, 24334170, 28802630). This variant is also known as delT1735. ClinVar contains an entry for this variant (Variation ID: 13674). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects ALPL function (PMID: 9814472, 15660230, 15794757). For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV003460475	SCV004191250	pathogenic	Adult hypophosphatasia	2024-02-19	criteria provided, single submitter	clinical testing
GeneDx	RCV000346130	SCV005442890	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with failure to localize to the cell surface and failure to rescue mineralization (PMID: 7833929, 9814472, 15794757); Frameshift variant predicted to result in abnormal protein length as the last 4 amino acids are replaced with 85 different amino acids; This variant is associated with the following publications: (PMID: 36217348, 32160374, 15794757, 9814472, 7833929, 24334170, 28802630, 29160033, 31014398, 30083035, 31707452, 31600233, 31641588, 31857675, 31787692, 23926372, 18455459, 15660230, 32547926, 33452237, 11810413, 12975786, 35024386, 35197081)
OMIM	RCV000014665	SCV000034920	pathogenic	Infantile hypophosphatasia	1998-12-01	no assertion criteria provided	literature only
GeneReviews	RCV000207209	SCV000262616	not provided	Hypophosphatasia		no assertion provided	literature only
Natera, Inc.	RCV000207209	SCV002094098	pathogenic	Hypophosphatasia	2021-05-14	no assertion criteria provided	clinical testing