Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Labcorp Genetics |
RCV001937924 | SCV002180942 | pathogenic | not provided | 2024-01-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 478 of the SLC12A1 protein (p.Gly478Arg). This variant is present in population databases (rs758166864, gnomAD 0.01%). This missense change has been observed in individual(s) with SLC12A1-related conditions (PMID: 9585600, 18391953, 29527380, 35348259; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1407973). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SLC12A1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. |
| Victorian Clinical Genetics Services, |
RCV003225202 | SCV003921777 | pathogenic | Bartter disease type 1 | 2022-09-02 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with Bartter syndrome, type 1 (MIM# 601678). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from glycine to arginine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (7 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0601 - Variant is located in the well-established functional AA permease domain (Decipher, Pfam). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0802 - This variant has moderate previous evidence of pathogenicity in unrelated individuals. This variant has been observed in two compound heterozygous, and a homozygous individual with Bartter syndrome (PMID: 18391953, PMID: 24902942, PMID: 9585600). It has also been reported once as VUS in ClinVar. (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1201 - Heterozygous variant detected in trans with a second pathogenic heterozygous variant (p.(Gln656*)) in a recessive disease. (SP) 1206 - This variant has been shown to be paternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
| Fulgent Genetics, |
RCV003225202 | SCV005632962 | likely pathogenic | Bartter disease type 1 | 2024-02-08 | criteria provided, single submitter | clinical testing |