ClinVar Miner

Submissions for variant NM_001126108.2(SLC12A3):c.56_57dup (p.Phe20fs)

dbSNP: rs758683818
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001055691 SCV001220091 pathogenic not provided 2024-02-07 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Phe20Alafs*8) in the SLC12A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SLC12A3 are known to be pathogenic (PMID: 20848653, 22009145, 25841442). This variant is present in population databases (rs758683818, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of Gitelman syndrome (PMID: 31285285). ClinVar contains an entry for this variant (Variation ID: 851316). For these reasons, this variant has been classified as Pathogenic.
New York Genome Center RCV001832505 SCV002097874 likely pathogenic Familial hypokalemia-hypomagnesemia 2020-06-05 criteria provided, single submitter clinical testing
Ambry Genetics RCV004678925 SCV005167301 likely pathogenic Inborn genetic diseases 2024-05-17 criteria provided, single submitter clinical testing The c.56_57dupGC (p.F20Afs*8) alteration, located in exon 1 (coding exon 1) of the SLC12A3 gene, consists of a duplication of GC at position 56, causing a translational frameshift with a predicted alternate stop codon after 8 amino acids. The predicted stop codon occurs in the 5' end of the SLC12A3 gene. Premature termination codons in the 5’ end of a gene have been reported to escape nonsense-mediated mRNA decay and/or lead to re-initiation (Rivas, 2015; Lindeboom, 2016; Rhee, 2017). Direct evidence for this alteration is unavailable; however, premature termination codons are typically deleterious in nature. Based on data from gnomAD, the GCGC allele has an overall frequency of 0.001% (2/282296) total alleles studied. The highest observed frequency was 0.014% (1/7216) of Other alleles. This variant has been reported homozygous and in conjunction with another SLC12A3 variant in individuals genetically diagnosed with Gitelman syndrome; however, clinical details were limited (Blanchard, 2015; Alexandru, 2020). Based on the available evidence, this alteration is classified as likely pathogenic.
Fulgent Genetics, Fulgent Genetics RCV001832505 SCV005639132 pathogenic Familial hypokalemia-hypomagnesemia 2024-01-06 criteria provided, single submitter clinical testing
Natera, Inc. RCV001832505 SCV002089317 pathogenic Familial hypokalemia-hypomagnesemia 2021-09-01 no assertion criteria provided clinical testing

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