Submissions for variant NM_000338.3(SLC12A1):c.347G>A (p.Arg116His)

gnomAD frequency: 0.00334  dbSNP: rs34819316

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	RCV000513713	SCV000609926	uncertain significance	not provided	2017-04-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000513713	SCV001099547	benign	not provided	2024-01-31	criteria provided, single submitter	clinical testing
Mendelics	RCV000989308	SCV001139583	likely benign	Bartter disease type 1	2019-05-28	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000989308	SCV001276646	uncertain significance	Bartter disease type 1	2017-04-27	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx	RCV000513713	SCV001802349	likely benign	not provided	2020-05-19	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 20219833, 17699451, 25422309, 31672324)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271518	SCV002556048	benign	not specified	2022-06-21	criteria provided, single submitter	clinical testing	Variant summary: SLC12A1 c.347G>A (p.Arg116His) results in a non-conservative amino acid change located in the Amino acid permease, N-terminal domain (IPR013612) 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 0.0034 in 280172 control chromosomes (gnomAD), including 7 homozygotes. The variant was found occurring predominantly at a frequency of 0.005 within the Non-Finnish European subpopulation in the gnomAD database, with 5 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in SLC12A1 causing Bartter Syndrome, Type 1 (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Six ClinVar submitters have assessed the variant since 2014: two classified the variant as VUS, one as likely pathogenic, two as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV002271518	SCV004847518	likely benign	not specified	2023-10-11	criteria provided, single submitter	clinical testing	The p.Arg116His variant in SLC12A1 has been classified as likely benign because it has been been identified in 0.5% (636/126808) of European chromosomes, including 7 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.2.1.1). This is frequency is greater than expected for a pathogenic allele in SLC12A to cause Bartter syndrome. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. ACMG/AMP Criteria applied: BS1, PP3.
Molecular Biology Laboratory, Fundació Puigvert	RCV000989308	SCV001425252	likely pathogenic	Bartter disease type 1	2020-02-01	flagged submission	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000513713	SCV001551527	uncertain significance	not provided		no assertion criteria provided	clinical testing	The SLC12A1 p.Arg116His variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs34819316) and in ClinVar (classified as a VUS by Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics). The variant was identified in control databases in 955 of 280172 chromosomes (7 homozygous) at a frequency of 0.003409 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Other in 38 of 7182 chromosomes (freq: 0.005291), European (non-Finnish) in 636 of 126808 chromosomes (freq: 0.005015), Ashkenazi Jewish in 49 of 10314 chromosomes (freq: 0.004751), Latino in 161 of 35394 chromosomes (freq: 0.004549), European (Finnish) in 46 of 25056 chromosomes (freq: 0.001836), African in 24 of 24958 chromosomes (freq: 0.000962) and South Asian in 1 of 30510 chromosomes (freq: 0.000033), but was not observed in the East Asian population. The p.Arg116 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003942673	SCV004766939	likely benign	SLC12A1-related disorder	2020-06-08	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).