Submissions for variant NM_000478.6(ALPL):c.648+1G>A

gnomAD frequency: 0.00001  dbSNP: rs749544042

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000710058	SCV000840440	pathogenic	Infantile hypophosphatasia	2017-01-02	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001227927	SCV001400306	pathogenic	not provided	2025-01-30	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 6 of the ALPL gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in ALPL are known to be pathogenic (PMID: 3174660, 10679946, 32973344, 33814268). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. Disruption of this splice site has been observed in individual(s) with hypophosphatasia (PMID: 9781036, 11745997, 19232125). ClinVar contains an entry for this variant (Variation ID: 13678). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001553715	SCV001774692	pathogenic	Hypophosphatasia	2021-07-30	criteria provided, single submitter	clinical testing	Variant summary: ALPL c.648+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 250046 control chromosomes (gnomAD). c.648+1G>A has been reported in the literature in multiple individuals in both compound heterozygous and heterozygous state affected with Hypophosphatasia (example: Angel_2020, Araci_2021, Krishnani_2021). These data indicate that the variant is very likely to be associated with disease. Reduced enzymatic activity was noted in both compound heterozygous and heterozygous patients carrying the variant (example: Angel_2020, Krishnani_2021). Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic in germline origin. Based on the evidence outlined above, the variant was classified as pathogenic.
DASA	RCV001553715	SCV002107114	pathogenic	Hypophosphatasia	2022-03-05	criteria provided, single submitter	clinical testing	The c.648+1G>A variant is located in a canonical splice-site, and it is not predicted the protein reading frame alteration, however, occur in a critical region and the variant disrupts >10% of the protein - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 13678; PMID: 19232125; PMID: 11745997; PMID: 9781036) - PS4. This variant is not present in population databases (rs749544042- gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. The c.648+1G>A was detected in trans with a pathogenic variant (PMID: 19232125; PMID: 9781036; PMID: 23454488) - PM3. 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.
GeneDx	RCV001227927	SCV002567455	pathogenic	not provided	2022-03-29	criteria provided, single submitter	clinical testing	Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 11745997, 29236161, 30249491, 31400546, 34662886, 30942483, 33601892, 33814268, 33101980, 9781036)
Baylor Genetics	RCV003466858	SCV004193698	pathogenic	Adult hypophosphatasia	2023-10-22	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005016264	SCV005644295	pathogenic	Adult hypophosphatasia; Childhood hypophosphatasia; Infantile hypophosphatasia	2023-12-23	criteria provided, single submitter	clinical testing
OMIM	RCV000014671	SCV000034926	pathogenic	Perinatal lethal hypophosphatasia	2001-10-15	no assertion criteria provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000710058	SCV000925826	pathogenic	Infantile hypophosphatasia	2018-12-12	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001553715	SCV002094064	pathogenic	Hypophosphatasia	2020-02-08	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004549368	SCV004749505	pathogenic	ALPL-related disorder	2024-03-05	no assertion criteria provided	clinical testing	The ALPL c.648+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant in the compound heterozygous state was previously reported to be pathogenic for autosomal recessive hypophosphatasia (Huggins. 2020. PubMed ID: 33101980; reported as c.658+1A, Mornet et al. 1998. PubMed ID: 9781036; Sergi et al. 2001. PubMed ID: 11745997; Mori et al. 2016. PubMed ID: 28580391). This variant in the heterozygous condition was reported in individuals with adults hypophosphatasia (Taillandier. 2018. PubMed ID: 29236161). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. Variants that disrupt the consensus splice donor site in ALPL are expected to be pathogenic. This variant is interpreted as pathogenic.