VCV000001429.12 - ClinVar

NM_001177316.2(SLC34A3):c.846G>A (p.Pro282=)

Germline

Classification

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.

(6)

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.

Conflicting classifications of pathogenicity
Pathogenic(1); Likely pathogenic(3); Uncertain significance(1)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_001177316.2(SLC34A3):c.846G>A (p.Pro282=)

Variation ID: 1429 Accession: VCV000001429.12

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q34.3 9: 137233722 (GRCh38) [ NCBI UCSC ] 9: 140128174 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Jul 12, 2015	Feb 14, 2024	Jan 11, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_001177316.2:c.846G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001170787.2:p.Pro282=	synonymous
NM_001177317.2:c.846G>A	NP_001170788.2:p.Pro282=	synonymous
NM_080877.3:c.846G>A	NP_543153.2:p.Pro282=	synonymous
NC_000009.12:g.137233722G>A
NC_000009.11:g.140128174G>A
NG_017008.2:g.7822G>A

... more HGVS ... less HGVS

Protein change

Other names

P282P

Canonical SPDI

NC_000009.12:137233721:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00020 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

Exome Aggregation Consortium (ExAC) 0.00003

The Genome Aggregation Database (gnomAD) 0.00004

1000 Genomes Project 0.00020

Links

ClinGen: CA115012 OMIM: 609826.0004 dbSNP: rs121918236 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help 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.
SLC34A3		-	-	GRCh38 GRCh37	607	724

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.
Autosomal recessive hypophosphatemic bone disease	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	Aug 11, 2021	RCV000001494.23
not provided	Likely pathogenic (1)	criteria provided, single submitter	Jan 11, 2024	RCV002512648.10

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.
Likely pathogenic (Jun 20, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Hypophosphatemic rickets with hypercalciuria Affected status: yes Allele origin: germline	Hadassah Hebrew University Medical Center Accession: SCV001430588.1 First in ClinVar: Aug 22, 2020 Last updated: Aug 22, 2020	Publications: PubMed (1) PubMed: 33223529
Uncertain significance (Jul 21, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal recessive hypophosphatemic bone disease Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003825681.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Likely pathogenic (Jan 11, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003441512.2 First in ClinVar: Feb 07, 2023 Last updated: Feb 14, 2024	Publications: PubMed (6) PubMed: 16358215‚ 31672324‚ 33223529‚ 34805638‚ 17576681‚ 9536098 Comment: This sequence change affects codon 282 of the SLC34A3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid … (more) This sequence change affects codon 282 of the SLC34A3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SLC34A3 protein. This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121918236, gnomAD 0.005%). This variant has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (PMID: 16358215, 31672324, 33223529, 34805638). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1429). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. (less)
Pathogenic (Sep 30, 2017)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	Autosomal recessive hypophosphatemic bone disease (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000608393.1 First in ClinVar: Oct 30, 2017 Last updated: Oct 30, 2017	Publications: PubMed (1) PubMed: 16358215 Observation 1: Sex: female Tissue: blood Observation 2: Sex: male Tissue: blood
Likely pathogenic (Aug 11, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing, in vitro	Autosomal recessive hypophosphatemic bone disease (Autosomal recessive inheritance) Affected status: not applicable, yes Allele origin: paternal, not applicable	Laboratory of Functional Genomics, Research Centre for Medical Genetics Accession: SCV001781032.1 First in ClinVar: Aug 18, 2021 Last updated: Aug 18, 2021	Comment: Synonymous variant c.846G>A in SLC34A3 could be classified as likely pathogenic variant according to ACMG criteria (PM2, PS3, PM3). The variant vas observed in 12 … (more) Synonymous variant c.846G>A in SLC34A3 could be classified as likely pathogenic variant according to ACMG criteria (PM2, PS3, PM3). The variant vas observed in 12 y.o. female patient with hypophosphatemic rickets with hypercalciuria in compound heterozygous state with c.1304delG variant in SLC34A3 gene. (less) Observation 1: Age: 10-19 years Sex: female Ethnicity/Population group: Russian Observation 2: Sex: female Tissue: fibroblasts Result: Variant led to disruption of donor splicing site and complete exon 8 of SLC34A3 skipping. Deletion of exon 8 resulted in 30 amino acids loss in extracellular domain.
Pathogenic (Feb 01, 2006)	no assertion criteria provided Method: literature only	HYPOPHOSPHATEMIC RICKETS WITH HYPERCALCIURIA, HEREDITARY Affected status: not provided Allele origin: germline	OMIM Accession: SCV000021649.2 First in ClinVar: Apr 04, 2013 Last updated: Jul 12, 2015	Publications: PubMed (1) PubMed: 16358215 Comment on evidence: For discussion of the pro282-to-pro (P282P) mutation in the SLC34A3 gene that was found in compound heterozygous state in 2 sibs with hypophosphatemic rickets with … (more) For discussion of the pro282-to-pro (P282P) mutation in the SLC34A3 gene that was found in compound heterozygous state in 2 sibs with hypophosphatemic rickets with hypercalciuria (HHRH; 241530) by Lorenz-Depiereux et al. (2006), see 609826.0003. (less)

Comment:

This sequence change affects codon 282 of the SLC34A3 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the SLC34A3 protein. This variant also falls at the last nucleotide of exon 8, which is part of the consensus splice site for this exon. This variant is present in population databases (rs121918236, gnomAD 0.005%). This variant has been observed in individual(s) with hypophosphatemic rickets with hypercalciuria (PMID: 16358215, 31672324, 33223529, 34805638). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 1429). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

Comment:

Synonymous variant c.846G>A in SLC34A3 could be classified as likely pathogenic variant according to ACMG criteria (PM2, PS3, PM3). The variant vas observed in 12 y.o. female patient with hypophosphatemic rickets with hypercalciuria in compound heterozygous state with c.1304delG variant in SLC34A3 gene.

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.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Comprehensive Genetic Analysis Reveals Complexity of Monogenic Urinary Stone Disease.	Cogal AG	Kidney international reports	2021	PMID: 34805638
Parental exome analysis identifies shared carrier status for a second recessive disorder in couples with an affected child.	Mor-Shaked H	European journal of human genetics : EJHG	2021	PMID: 33223529
High-throughput sequencing contributes to the diagnosis of tubulopathies and familial hypercalcemia hypocalciuria in adults.	Hureaux M	Kidney international	2019	PMID: 31672324
Aberrant 5' splice sites in human disease genes: mutation pattern, nucleotide structure and comparison of computational tools that predict their utilization.	Buratti E	Nucleic acids research	2007	PMID: 17576681
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
Statistical features of human exons and their flanking regions.	Zhang MQ	Human molecular genetics	1998	PMID: 9536098

Text-mined citations for rs121918236 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_001177316.2(SLC34A3):c.846G>A (p.Pro282=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs121918236 ...