NM_001126108.2(SLC12A3):c.1928C>T (p.Pro643Leu) AND not provided

Germline classification:: Pathogenic/Likely pathogenic (6 submissions)
Last evaluated:: Apr 22, 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:: RCV000681948.16

Allele description [Variation Report for NM_001126108.2(SLC12A3):c.1928C>T (p.Pro643Leu)]

NM_001126108.2(SLC12A3):c.1928C>T (p.Pro643Leu)

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.1928C>T (p.Pro643Leu)

HGVS:

NC_000016.10:g.56886366C>T
NG_009386.1:g.26160C>T
NM_000339.3:c.1928C>T
NM_001126107.2:c.1925C>T
NM_001126108.2:c.1928C>TMANE SELECT
NP_000330.3:p.Pro643Leu
NP_001119579.2:p.Pro642Leu
NP_001119580.2:p.Pro643Leu
NC_000016.9:g.56920278C>T
NM_000339.2:c.1928C>T
NM_001126108.1:c.1928C>T
NM_001126108.2:c.1928C>T
p.(Pro643Leu)

Protein change:

P642L

Links:

dbSNP: rs140012781

NCBI 1000 Genomes Browser:

rs140012781

Molecular consequence:

NM_000339.3:c.1928C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126107.2:c.1925C>T - missense variant - [Sequence Ontology: SO:0001583]
NM_001126108.2:c.1928C>T - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Synonyms:: none provided
Identifiers:: MedGen: C3661900

Recent activity

Clear Turn Off Turn On

MULTISPECIES: CAP domain-containing protein [Bacillus]
MULTISPECIES: CAP domain-containing protein [Bacillus]
gi|504292611|ref|WP_014479713.1|

Protein
Mus musculus axin interactor, dorsalization associated, mRNA (cDNA clone IMAGE:2...
Mus musculus axin interactor, dorsalization associated, mRNA (cDNA clone IMAGE:2651163)
gi|13436007|gb|BC004835.1|

Nucleotide

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

Help

Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000565567	GeneDx	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Pathogenic (Apr 22, 2024)	germline	clinical testing	Citation Link,
SCV000809436	Gharavi Laboratory, Columbia University	no assertion criteria provided (ACMG Guidelines, 2015)	Pathogenic (Sep 16, 2018)	germline	research	PubMed (1) [See all records that cite this PMID]
SCV001576570	Labcorp Genetics (formerly Invitae), Labcorp	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Likely pathogenic (Jan 31, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 11168953, 11940055, 17654016, 21753071, 22169961, 28492532
SCV001879512	Athena Diagnostics	criteria provided, single submitter (Athena Diagnostics criteria)	Pathogenic (Dec 22, 2020)	unknown	clinical testing	PubMed (13) [See all records that cite these PMIDs] 28947054, 22169961, 22009145, 11940055, 32129221, 31672324, 19349556, 21753071, 17654016, 15976513, 21415153, 11168953, 26467025
SCV001928624	Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Pathogenic	germline	clinical testing
SCV001957402	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus See additional submitters Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	no assertion criteria provided	Likely pathogenic	germline	clinical testing

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, research
not provided	germline	unknown	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

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, Kobayashi Y, Patil N, Thusberg J, Westbrook M; Invitae Clinical Genomics Group., Topper S.

Genet Med. 2017 Oct;19(10):1105-1117. doi: 10.1038/gim.2017.37. Epub 2017 May 11. Erratum in: Genet Med. 2020 Jan;22(1):240. doi: 10.1038/s41436-019-0624-9.

PubMed [citation]

PMID:: 28492532
PMCID:: PMC5632818

See all PubMed Citations (15)

Details of each submission

From GeneDx, SCV000565567.8

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

Description

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22169961, 11940055, 17654016, 19349556, 11168953, 15976513, 21753071, 22009145, 28947054, 21415153, 33585337, 31672324, 32129221, 34426522, 35753512, 35327948, 30476936, 25990047, 37078890, 37537162, Gozetici2022[CaseReport], 35628451)

#	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 Gharavi Laboratory, Columbia University, SCV000809436.1

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

#	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 Labcorp Genetics (formerly Invitae), Labcorp, SCV001576570.4

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 643 of the SLC12A3 protein (p.Pro643Leu). This variant is present in population databases (rs140012781, gnomAD 0.2%). This missense change has been observed in individuals with Gitelman syndrome (PMID: 11168953, 11940055, 17654016, 21753071, 22169961). ClinVar contains an entry for this variant (Variation ID: 417863). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

#	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 Athena Diagnostics, SCV001879512.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (13)

Description

This variant is statistically more frequent in affected individuals than in the general population and/or healthy controls and therefore is consistent with pathogenicity (http://gnomad.broadinstitute.org). In multiple individuals, this variant has been seen with a single recessive pathogenic variant in the same gene, suggesting this variant may also be pathogenic. Computational tools predict that this variant is damaging.

#	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 Genome Diagnostics Laboratory, University Medical Center Utrecht - VKGL Data-share Consensus, SCV001928624.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ - VKGL Data-share Consensus, SCV001957402.1

#	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	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Oct 20, 2024

ClinVar

Relating variation to medicine