Submissions for variant NM_001177316.2(SLC34A3):c.448+1G>A

gnomAD frequency: 0.00017  dbSNP: rs150841256

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000514313	SCV000610299	pathogenic	not provided	2017-09-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000514313	SCV000709851	likely pathogenic	not provided	2017-12-19	criteria provided, single submitter	clinical testing	The c.448+1G>A variant in the SLC34A3 gene has been reported previously, using alternate nomenclature g.1226G>A, in an individual with HHRH who was compound heterozygous for c.448+1G>A and another SLC34A3 variant (Phulwani et al., 2011). RT-PCR studies of c.448+1G>A indicate that it creates an alternative splice donor site upstream of the natural splice donor site in intron 5, leading to a frameshift and a truncated transcript (Phulwani et al., 2011). The c.448+1G>A variant is observed in 35/118640 (0.03%) alleles from individuals of non-Finnish European background and in 39/261838 (0.015%) total alleles, including one homozygous individual, in large population cohorts (Lek et al., 2016). We interpret c.448+1G>A as a likely pathogenic variant.
Mayo Clinic Laboratories, Mayo Clinic	RCV000681630	SCV000809073	likely pathogenic	Autosomal recessive hypophosphatemic bone disease	2018-04-04	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000514313	SCV000856151	likely pathogenic	not provided	2017-08-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000514313	SCV001228352	pathogenic	not provided	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the SLC34A3 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 SLC34A3 are known to be pathogenic (PMID: 16358214, 16358215, 22159077). This variant is present in population databases (rs150841256, gnomAD 0.03%), including at least one homozygous and/or hemizygous individual. Disruption of this splice site has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (PMID: 21344632, 31440709). ClinVar contains an entry for this variant (Variation ID: 445687). 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.
Centogene AG - the Rare Disease Company	RCV000681630	SCV001424489	pathogenic	Autosomal recessive hypophosphatemic bone disease		criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000681630	SCV001752455	pathogenic	Autosomal recessive hypophosphatemic bone disease	2024-06-19	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000514313	SCV004032912	pathogenic	not provided	2023-08-01	criteria provided, single submitter	clinical testing	SLC34A3: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000681630	SCV005398945	pathogenic	Autosomal recessive hypophosphatemic bone disease	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with hypophosphatemic rickets with hypercalciuria (MIM#241530). (I) 0108 - This gene is associated with both recessive and dominant disease. Monoallelic inheritance has been reported in association with mild hypercalciuria, mild hypophosphatemia, and an absence of rickets or bone disease (OMIM; PMIDs: 16358214, 22806288, 21344632). (I) 0115 - Variants in this gene are known to have variable expressivity. Approximately 45% of compound heterozygotes present with rickets (PMID: 32524022). (I) 0211 - Canonical splice site variant without proven consequence on splicing (no functional evidence available). RT-PCR on lymphoblastoid cells of an affected compound heterozygous individual suggests this variant results in deletion of the the first 22 nucleotides in exon 5, predicted to cause a frameshift and truncated protein. However, data was not shown (PMID: 21344632). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 39 heterozygotes, 1 homozygote). (SP) 0311 - An alternative nucleotide change at the same canonical splice site is present in gnomAD (v3) (2 heterozygotes, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0704 - Another splice variant comparable to the one identified in this case has limited previous evidence for pathogenicity. The c.448+5G>A variant has been reported in three related individuals, a homozygous father with hereditary hypophosphatemic rickets with hypercalciuria and two male heterozygous offspring presenting with mild hypercalciuria (PMID: 22806288). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in compound heterozygous and heterozygous individuals with hereditary hypophosphatemic rickets with hypercalciuria (PMIDs: 21344632, 34805638; 31440709). It has also been reported as pathogenic/likely pathogenic by multiple clinical laboratories (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign