Submissions for variant NM_001177316.2(SLC34A3):c.756G>A (p.Gln252=)

gnomAD frequency: 0.00149  dbSNP: rs121918239

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV002254899	SCV002526245	uncertain significance	not provided	2024-11-06	criteria provided, single submitter	clinical testing	Alters the last nucleotide of the exon and is predicted to destroy the splice donor site and result in aberrant splicing; This variant is associated with the following publications: (PMID: 34805638, 16358214, 34426522, 31589614, 31672324, 33716164, 33226606, 33852231, 36699160, 35689455, 16849419)
Fulgent Genetics, Fulgent Genetics	RCV000001499	SCV002777683	uncertain significance	Autosomal recessive hypophosphatemic bone disease	2022-04-16	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV002254899	SCV003263493	benign	not provided	2024-01-30	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000001499	SCV003800440	uncertain significance	Autosomal recessive hypophosphatemic bone disease	2022-03-31	criteria provided, single submitter	clinical testing	The SLC34A3 c.756G>A; p.Gln252= variant (rs121918239) is described in the literature in 3 affected individuals who also carried an additional SLC34A3 variant (Hureaux 2019, Ichikawa 2006, Vaisitti 2021). The variant is listed in the ClinVar database (Variation ID: 1434) and is reported in the South Asian population with an allele frequency of 0.7% (211/28,892 alleles including 2 homozygotes) in the Genome Aggregation Database. This is a synonymous variant in the last nucleotide of exon 7, a moderately conserved nucleotide, and computational analyses (Alamut v.2.11) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. However, given the lack of functional data and the relatively high population frequency, the significance of the p.Gln252= variant is uncertain at this time. References: Hureaux M et al. High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults. Kidney Int. 2019 Dec;96(6):1408-1416. PMID: 31672324. Ichikawa S et al. Intronic deletions in the SLC34A3 gene cause hereditary hypophosphatemic rickets with hypercalciuria. J Clin Endocrinol Metab. 2006 Oct;91(10):4022-7. PMID: 16849419. Vaisitti T et al. Clinical exome sequencing is a powerful tool in the diagnostic flow of monogenic kidney diseases: an Italian experience. J Nephrol. 2021 Oct;34(5):1767-1781. PMID: 33226606.
CeGaT Center for Human Genetics Tuebingen	RCV002254899	SCV003917750	likely benign	not provided	2023-02-01	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003993727	SCV004813355	likely benign	not specified	2024-02-27	criteria provided, single submitter	clinical testing	Variant summary: SLC34A3 c.756G>A (p.Gln252Gln) alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens the canonical 5' donor site. One predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0024 in 216202 control chromosomes, predominantly at a frequency of 0.0073 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC34A3 causing Hereditary Hypophosphatemic Rickets With Hypercalciuria phenotype (0.0018), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.756G>A has been reported in the literature in individuals affected with Hereditary Hypophosphatemic Rickets With Hypercalciuria and renal hypophosphatemia (example, Hureaux_2019, Ichikawa_2006, Karakilic-Ozturan_2023, Sturznickel_2022), without strong evidence for causality. These data do not allow any conclusion about variant significance. Co-occurrences with other pathogenic variant(s) have been reported (SLC34A3 c.586G>A, p.Gly196Arg at a homozygous state with the homozygous variant of interest in a patient with HHRH), providing supporting evidence for a benign role (Sturznickel_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 31672324, 16849419, 36699160, 35689455). ClinVar contains an entry for this variant (Variation ID: 1434). Based on the evidence outlined above, the variant was classified as likely benign.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000001499	SCV005086782	uncertain significance	Autosomal recessive hypophosphatemic bone disease	2023-07-17	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. 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) 0106 - This gene is associated with autosomal recessive disease. (I) 0115 - Variants in this gene are known to have variable expressivity. Approximately 45% of compound heterozygotes present with rickets (PMID: 32524022). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). The substitution affects the last nucleotide of exon 7. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 558 heterozygotes, 2 homozygotes). (SP) 0508 - In silico predictions for abnormal splicing are conflicting. (I) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable non-canonical splice site variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. It has been reported in a single compound heterozygous proband with hypophosphatemic rickets with hypercalciuria (MIM#241530). However, only this gene was sequenced and RNA studies were not done to conclusively prove that this otherwise synonymous variant, leads to aberrant splicing (PMID: 16849419). This variant has also been reported in a kidney disease patient for whom another causative variant was identified (PMID: 33226606). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000001499	SCV000021654	pathogenic	Autosomal recessive hypophosphatemic bone disease	2006-10-01	no assertion criteria provided	literature only
Reproductive Health Research and Development, BGI Genomics	RCV000001499	SCV001142407	uncertain significance	Autosomal recessive hypophosphatemic bone disease	2020-01-06	no assertion criteria provided	curation	NM_080877.2:c.756G>A in the SLC34A3 gene has an allele frequency of 0.007 in South Asian subpopulation in the gnomAD database. It is a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site and the nucleotide is not highly conserved. One affected individual with hereditary hypophosphatemic rickets with hypercalciuria was a compound heterozygote for this variant and an 85-bp deletion in intron 10 (PMID: 16849419). We interpret it as variant of uncertain significance (VUS). ACMG/AMP criteria applied: BP7, PM3, PP4.
PreventionGenetics, part of Exact Sciences	RCV004745139	SCV005345323	uncertain significance	SLC34A3-related disorder	2024-03-07	no assertion criteria provided	clinical testing	The SLC34A3 c.756G>A variant is not predicted to result in an amino acid change (p.=). This variant occurs at the last base of exon 7 and is predicted to alter splicing by splicing prediction programs. It has been reported in patients affected by hereditary hypophosphatemic rickets with hypercalciuria (HHRH) and suspected to affect normal splicing, but no experimental evidence was presented to support a splice effect (Ichikawa et al. 2006. PubMed ID: 16849419, reported as g.1702G>A; Bergwitz et al. 2006. PubMed ID: 16358214; Hureaux et al 2019. PubMed ID: 31672324). In the Ichikawa et al. study, the c.756G>A (p.Gln252Gln) variant was found in a compound heterozygous state with a suspected pathogenic 85bp deletion in intron 10 in a patient with HHRH. This variant is reported in 0.73% of alleles in individuals of South Asian descent in gnomAD. Although we suspect that this variant may be a benign, we classify c.756G>A (p.Gln252Gln) as a variant of uncertain significance due to insufficient and conflicting evidence.