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.
ClinVar Genomic variation as it relates to human health
NM_001177316.2(SLC34A3):c.448+1G>A
Germline
Classification
Help
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.
(8)
Help
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.
Pathogenic/Likely pathogenic
8
criteria provided, multiple submitters, no conflicts
Somatic
No data submitted for somatic clinical impact
Somatic
No data submitted for oncogenicity
Variant Details
- Identifiers
-
NM_001177316.2(SLC34A3):c.448+1G>A
Variation ID: 445687 Accession: VCV000445687.32
- Type and length
-
single nucleotide variant, 1 bp
- Location
-
Cytogenetic: 9q34.3 9: 137232928 (GRCh38) [ NCBI UCSC ] 9: 140127380 (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 Nov 5, 2017 Oct 20, 2024 Jan 24, 2024 - HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001177316.2:c.448+1G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
splice donor NM_001177317.2:c.448+1G>A splice donor NM_080877.3:c.448+1G>A splice donor NC_000009.12:g.137232928G>A NC_000009.11:g.140127380G>A NG_017008.2:g.7028G>A - Protein change
- -
- Other names
- -
- Canonical SPDI
- NC_000009.12:137232927:G:A
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
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.
- -
-
Allele frequency
Help
The frequency of the allele represented by this VCV record.
-
The Genome Aggregation Database (gnomAD), exomes 0.00016
The Genome Aggregation Database (gnomAD) 0.00017
Exome Aggregation Consortium (ExAC) 0.00021
Trans-Omics for Precision Medicine (TOPMed) 0.00021
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00023
- Links
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 | ||
|---|---|---|---|---|---|---|
| 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 |
606 | 723 | |
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. |
|---|---|---|---|---|
| Pathogenic/Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
|
Jan 24, 2024 | RCV000514313.31 | |
| Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
|
Mar 18, 2022 | RCV000681630.19 |
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. |
|
|---|---|---|---|---|---|
|
Pathogenic
(Sep 25, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000610299.1
First in ClinVar: Nov 05, 2017 Last updated: Nov 05, 2017 |
|
|
|
Likely pathogenic
(Apr 04, 2018)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive hypophosphatemic bone disease
Affected status: unknown
Allele origin:
maternal
|
Mayo Clinic Laboratories, Mayo Clinic
Accession: SCV000809073.1
First in ClinVar: Sep 30, 2018 Last updated: Sep 30, 2018 |
|
|
|
Likely pathogenic
(Aug 07, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Eurofins Ntd Llc (ga)
Accession: SCV000856151.1
First in ClinVar: Dec 15, 2018 Last updated: Dec 15, 2018 |
Number of individuals with the variant: 1
Sex: mixed
|
|
|
Likely pathogenic
(Dec 19, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000709851.2
First in ClinVar: Apr 02, 2018 Last updated: Dec 15, 2018 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: clinical testing
|
Hypophosphatemic rickets with hypercalciuria
Affected status: yes
Allele origin:
germline
|
Centogene AG - the Rare Disease Company
Accession: SCV001424489.1
First in ClinVar: Jul 26, 2020 Last updated: Jul 26, 2020 |
|
|
|
Pathogenic
(Mar 18, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Autosomal recessive hypophosphatemic bone disease
Affected status: unknown
Allele origin:
unknown
|
Fulgent Genetics, Fulgent Genetics
Accession: SCV001752455.2
First in ClinVar: Jul 18, 2021 Last updated: Dec 31, 2022 |
|
|
|
Pathogenic
(Jan 24, 2024)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: unknown
Allele origin:
germline
|
Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV001228352.5
First in ClinVar: Apr 15, 2020 Last updated: Feb 14, 2024 |
Comment:
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 … (more)
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. (less)
|
|
|
Pathogenic
(Aug 01, 2023)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
|
CeGaT Center for Human Genetics Tuebingen
Accession: SCV004032912.11
First in ClinVar: Sep 16, 2023 Last updated: Oct 20, 2024 |
Comment:
SLC34A3: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting
Number of individuals with the variant: 1
|
Comment:
Comment:
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.
Comment:
SLC34A3: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting
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:
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.
Comment:
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.
Comment:
SLC34A3: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Description of 5 Novel SLC34A3/NPT2c Mutations Causing Hereditary Hypophosphatemic Rickets With Hypercalciuria. | Chen A | Kidney international reports | 2019 | PMID: 31440709 |
| Processing and stability of type IIc sodium-dependent phosphate cotransporter mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria. | Haito-Sugino S | American journal of physiology. Cell physiology | 2012 | PMID: 22159077 |
| Hereditary hypophosphatemic rickets with hypercalciuria and nephrolithiasis-identification of a novel SLC34A3/NaPi-IIc mutation. | Phulwani P | American journal of medical genetics. Part A | 2011 | PMID: 21344632 |
| 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 |
| Splicing in action: assessing disease causing sequence changes. | Baralle D | Journal of medical genetics | 2005 | PMID: 16199547 |
| http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=SLC34A3 | - | - | - | - |
Text-mined citations for rs150841256 ...
HelpThese 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 19, 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.