ClinVar Genomic variation as it relates to human health
NM_001177316.2(SLC34A3):c.575C>T (p.Ser192Leu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001177316.2(SLC34A3):c.575C>T (p.Ser192Leu)
Variation ID: 198610 Accession: VCV000198610.20
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q34.3 9: 137233223 (GRCh38) [ NCBI UCSC ] 9: 140127675 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Oct 30, 2017 Mar 16, 2024 Jan 22, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001177316.2:c.575C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001170787.2:p.Ser192Leu missense NM_001177317.2:c.575C>T NP_001170788.2:p.Ser192Leu missense NM_080877.3:c.575C>T NP_543153.2:p.Ser192Leu missense NC_000009.12:g.137233223C>T NC_000009.11:g.140127675C>T NG_017008.2:g.7323C>T Q8N130:p.Ser192Leu - Protein change
- S192L
- Other names
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- Canonical SPDI
- NC_000009.12:137233222:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00040
The Genome Aggregation Database (gnomAD), exomes 0.00044
Trans-Omics for Precision Medicine (TOPMed) 0.00053
The Genome Aggregation Database (gnomAD) 0.00059
Exome Aggregation Consortium (ExAC) 0.00090
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
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Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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SLC34A3 | - | - |
GRCh38 GRCh37 |
588 | 673 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (4) |
criteria provided, multiple submitters, no conflicts
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Sep 1, 2022 | RCV000513414.11 | |
Pathogenic (7) |
criteria provided, multiple submitters, no conflicts
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Jan 22, 2024 | RCV000681813.14 | |
Pathogenic (1) |
criteria provided, single submitter
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Jan 4, 2024 | RCV003927693.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Pathogenic
(Sep 30, 2017)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive hypophosphatemic bone disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline,
maternal
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Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München
Accession: SCV000608392.1
First in ClinVar: Oct 30, 2017 Last updated: Oct 30, 2017 |
Observation 1:
Tissue: blood
Observation 2:
Sex: male
Tissue: blood
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Pathogenic
(Feb 17, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000700779.2
First in ClinVar: Oct 30, 2017 Last updated: Oct 01, 2018 |
Number of individuals with the variant: 2
Sex: mixed
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Pathogenic
(Nov 30, 2019)
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criteria provided, single submitter
Method: clinical testing
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Not provided
Affected status: unknown
Allele origin:
germline
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Blueprint Genetics
Accession: SCV001832332.1
First in ClinVar: Sep 08, 2021 Last updated: Sep 08, 2021 |
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Likely pathogenic
(May 24, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive hypophosphatemic bone disease
Affected status: yes
Allele origin:
germline
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MGZ Medical Genetics Center
Accession: SCV002579921.1
First in ClinVar: Oct 15, 2022 Last updated: Oct 15, 2022 |
Number of individuals with the variant: 1
Sex: female
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Pathogenic
(Sep 02, 2021)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV002013755.2
First in ClinVar: Nov 12, 2021 Last updated: Mar 04, 2023 |
Comment:
Likely a European founder mutation that has been associated with a less severe HHRH phenotype in the homozygous state and increased risk for renal calcifications … (more)
Likely a European founder mutation that has been associated with a less severe HHRH phenotype in the homozygous state and increased risk for renal calcifications in the heterozygous state (Iancu et al., 2020); Published functional studies demonstrate that although this variant does not have a significant impact on membrane sorting of phosphate, it severely reduces transport activity (Schnauer et al., 2019); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 16358214, 32150856, 24700880, 30798342, 19820004, 18996815, 16358215, 32155322, 31672324) (less)
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Pathogenic
(Nov 05, 2020)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive hypophosphatemic bone disease
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Division Of Personalized Genomic Medicine, Columbia University Irving Medical Center
Accession: SCV004190152.1
First in ClinVar: Dec 24, 2023 Last updated: Dec 24, 2023 |
Comment:
The c.575C>T variant in the SLC34A3 gene is a homozygous missense variant, which results in the substitution of the a serine residue at the 192 … (more)
The c.575C>T variant in the SLC34A3 gene is a homozygous missense variant, which results in the substitution of the a serine residue at the 192 position to leucine (p.Ser192Leu). This variant localizes to coding exon 7 of the SLC34A3 gene (13 exons total; NM_080877. In- silico analyses are inconsistent regarding predictions of the effect of this variant on protein structure and/or function (PROVEAN: neutral SIFT: damaging; PolyPhen-2: benign). This variant has been observed in the Genome Aggregation Database (gnomAD) at a low frequency (allele frequency = 0.0004615, no homozygotes), indicating it is not a common benign variant in the populations represented in this database. This variant has been reported to segregate with disease in multiple individuals with HHRH either in the homozygous state or with another SLC34A3 variant (PMIDs: 19820004, 18996815, 16358215, 16358214, 30798342). A different missense change at the same amino acid residue (S192W) has been described to be disease causing. (less)
Clinical Features:
Stage 3 chronic kidney disease (present)
Age: 30-39 years
Sex: female
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Pathogenic
(Sep 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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Autosomal recessive hypophosphatemic bone disease
Affected status: unknown
Allele origin:
germline
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Revvity Omics, Revvity
Accession: SCV002023556.3
First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024 |
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Pathogenic
(Jan 22, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV001210798.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 192 of the SLC34A3 protein (p.Ser192Leu). … (more)
This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 192 of the SLC34A3 protein (p.Ser192Leu). This variant is present in population databases (rs199690076, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (HHRH) (PMID: 16358214, 18996815, 19820004). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 198610). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SLC34A3 protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. (less)
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Pathogenic
(Jan 04, 2024)
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criteria provided, single submitter
Method: clinical testing
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SLC34A3-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004753038.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
The SLC34A3 c.575C>T variant is predicted to result in the amino acid substitution p.Ser192Leu. This variant was reported in patients with hereditary hypophosphatemic rickets with … (more)
The SLC34A3 c.575C>T variant is predicted to result in the amino acid substitution p.Ser192Leu. This variant was reported in patients with hereditary hypophosphatemic rickets with hypercalciuria (Bergwitz et al. 2006. PubMed ID: 16358214; Lorenz-Depiereux et al. 2006. PubMed ID: 16358215; Page et al. 2008. PubMed ID: 18996815; Tencza et al. 2009. PubMed ID: 19820004; Schönauer et al. 2019. PubMed ID: 30798342; Table S1, Hureaux et al. 2019. PubMed ID: 31672324). Of note, some individuals heterozygous for this particular variant present with milder hypercalciuria and some signs of renal calcification (Tencza et al. 2009. PubMed ID: 19820004; Schönauer et al. 2019. PubMed ID: 30798342). This variant is reported in 0.096% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. (less)
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Likely pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809284.1
First in ClinVar: Oct 01, 2018 Last updated: Oct 01, 2018 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, University Medical Center Utrecht
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001977883.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Likely pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001979394.1 First in ClinVar: Oct 16, 2021 Last updated: Oct 16, 2021 |
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Evaluating pathogenicity of SLC34A3-Ser192Leu, a frequent European missense variant in disorders of renal phosphate wasting. | Schönauer R | Urolithiasis | 2019 | PMID: 30798342 |
Hypophosphatemic rickets with hypercalciuria due to mutation in SLC34A3/type IIc sodium-phosphate cotransporter: presentation as hypercalciuria and nephrolithiasis. | Tencza AL | The Journal of clinical endocrinology and metabolism | 2009 | PMID: 19820004 |
A patient with hypophosphatemia, a femoral fracture, and recurrent kidney stones: report of a novel mutation in SLC34A3. | Page K | Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists | 2008 | PMID: 18996815 |
Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. | Lorenz-Depiereux B | American journal of human genetics | 2006 | PMID: 16358215 |
SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis. | Bergwitz C | American journal of human genetics | 2006 | PMID: 16358214 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC34A3 | - | - | - | - |
Text-mined citations for rs199690076 ...
HelpRecord last updated Apr 20, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.