NM_001177316.2(SLC34A3):c.448+1G>A AND not provided

Germline classification:: Pathogenic/Likely pathogenic (5 submissions)
Last evaluated:: Jan 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000514313.24

Allele description [Variation Report for NM_001177316.2(SLC34A3):c.448+1G>A]

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

Gene:

SLC34A3:solute carrier family 34 member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.3

Genomic location:

Preferred name:

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

HGVS:

NC_000009.12:g.137232928G>A
NG_017008.2:g.7028G>A
NM_001177316.2:c.448+1G>AMANE SELECT
NM_001177317.2:c.448+1G>A
NM_080877.3:c.448+1G>A
NC_000009.11:g.140127380G>A
NM_001177316.1:c.448+1G>A
NM_001177317.1:c.448+1G>A
NM_080877.2:c.448+1G>A

Links:

dbSNP: rs150841256

NCBI 1000 Genomes Browser:

rs150841256

Molecular consequence:

NM_001177316.2:c.448+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_001177317.2:c.448+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]
NM_080877.3:c.448+1G>A - splice donor variant - [Sequence Ontology: SO:0001575]

Observations:

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000610299	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 25, 2017)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV000709851	GeneDx	criteria provided, single submitter (GeneDx Variant Classification (06012015))	Likely pathogenic (Dec 19, 2017)	germline	clinical testing	Citation Link,
SCV000856151	Eurofins Ntd Llc (ga)	criteria provided, single submitter (EGL Classification Definitions 2015)	Likely pathogenic (Aug 7, 2017)	germline	clinical testing	Citation Link,
SCV001228352	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 16199547, 16358214, 16358215, 22159077, 21344632, 31440709, 28492532
SCV004032912	CeGaT Center for Human Genetics Tuebingen	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	Pathogenic (Aug 1, 2023)	germline	clinical testing	Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Splicing in action: assessing disease causing sequence changes.

Baralle D, Baralle M.

J Med Genet. 2005 Oct;42(10):737-48. Review.

PubMed [citation]

PMID:: 16199547
PMCID:: PMC1735933

See all PubMed Citations (8)

Details of each submission

From Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, SCV000610299.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	0.000554	not provided	not provided

From GeneDx, SCV000709851.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	not provided

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Eurofins Ntd Llc (ga), SCV000856151.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		1	not provided	not provided	not provided

From Invitae, SCV001228352.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

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.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From CeGaT Center for Human Genetics Tuebingen, SCV004032912.5

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	1	not provided	not provided	clinical testing	not provided

Description

SLC34A3: PM3:Very Strong, PVS1:Strong, PM2:Supporting, PS3:Supporting

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: May 7, 2024

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