NM_001126108.2(SLC12A3):c.2954G>A (p.Cys985Tyr) AND Familial hypokalemia-hypomagnesemia

Germline classification:: Conflicting interpretations of pathogenicity (7 submissions)
Last evaluated:: Jan 27, 2023
Review status:: criteria provided, conflicting classifications

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:: RCV001271446.20

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.2954G>A (p.Cys985Tyr)]

NM_001126108.2(SLC12A3):c.2954G>A (p.Cys985Tyr)

Genes:

LOC126862361:CDK7 strongly-dependent group 2 enhancer GRCh37_chr16:56946332-56947531 [Gene]
SLC12A3:solute carrier family 12 member 3 [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

16q13

Genomic location:

Preferred name:

NM_001126108.2(SLC12A3):c.2954G>A (p.Cys985Tyr)

HGVS:

NC_000016.10:g.56913293G>A
NG_009386.1:g.53087G>A
NM_000339.3:c.2981G>A
NM_001126107.2:c.2978G>A
NM_001126108.2:c.2954G>AMANE SELECT
NP_000330.3:p.Cys994Tyr
NP_001119579.2:p.Cys993Tyr
NP_001119580.2:p.Cys985Tyr
NC_000016.9:g.56947205G>A
NM_000339.2:c.2981G>A
NM_001126108.2:c.2954G>A
p.CYS994TYR

Protein change:

C985Y

Links:

dbSNP: rs199849117

NCBI 1000 Genomes Browser:

rs199849117

Molecular consequence:

NM_000339.3:c.2981G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126107.2:c.2978G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_001126108.2:c.2954G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Familial hypokalemia-hypomagnesemia (GTLMNS)
Synonyms:: Potassium and magnesium depletion; Hypomagnesemia-hypokalemia, primary renotubular, with hypocalciuria
Identifiers:: MONDO: MONDO:0009904; MedGen: C0268450; Orphanet: 358; OMIM: 263800

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV001452599	Natera, Inc.	no assertion criteria provided	Pathogenic (Sep 16, 2020)	germline	clinical testing
SCV001752474	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jun 30, 2021)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002020626	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Aug 30, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002055359	Genome-Nilou Lab	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jul 15, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002103054	Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn	criteria provided, single submitter (ACMG Guidelines, 2015)	Uncertain significance (Nov 11, 2021)	inherited	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002513829	European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 27, 2022)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV003800734	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Jan 27, 2023)	germline	clinical testing	PubMed (3) [See all records that cite these PMIDs] 29398133, 22009145, 12039972 Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	no	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	inherited	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	unknown	unknown	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

Simultaneous sequencing of 37 genes identified causative mutations in the majority of children with renal tubulopathies.

Ashton EJ, Legrand A, Benoit V, Roncelin I, Venisse A, Zennaro MC, Jeunemaitre X, Iancu D, Van't Hoff WG, Walsh SB, Godefroid N, Rotthier A, Del Favero J, Devuyst O, Schaefer F, Jenkins LA, Kleta R, Dahan K, Vargas-Poussou R, Bockenhauer D.

Kidney Int. 2018 Apr;93(4):961-967. doi: 10.1016/j.kint.2017.10.016. Epub 2018 Feb 15.

PubMed [citation]

PMID:: 29398133

See all PubMed Citations (4)

Details of each submission

From Natera, Inc., SCV001452599.1

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

From Fulgent Genetics, Fulgent Genetics, SCV001752474.1

#	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	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002020626.3

#	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	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Genome-Nilou Lab, SCV002055359.1

#	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	no	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Institute of Human Genetics, Clinical Exome/Genome Diagnostics Group, University Hospital Bonn, SCV002103054.1

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

Description

PS3_moderate, PS4_moderate

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

From European Hospital Georges Pompidou Genetics Department, Assistance Publique - Hôpitaux de Paris AP-HP, SCV002513829.1

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

Description

ACMG criteria used:PS4 PS3 PM1 PM2 PM3 PP3 PP5

#	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 Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV003800734.2

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (3)

Description

Variant summary: SLC12A3 c.2981G>A (p.Cys994Tyr) results in a non-conservative amino acid change located in the SLC12A transporter, C-terminal domain (IPR018491) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251292 control chromosomes. This frequency does not allow conclusions about variant significance. c.2981G>A has been reported in the literature as a biallelic genotype in multiple individuals affected with Familial Hypokalemia-Hypomagnesemia (Gitelman Syndrome) (example, PMID: 22009145, 29398133). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example, PMID: 12039972), demonstrating significantly reduced metolazone-sensitive (22)Na(+) uptake relative to the wild-type thereby impacting functional outcomes. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Pathogenic, n=9). Based on the evidence outlined above, the variant was 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

Last Updated: May 12, 2024

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