ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3995C>T (p.Pro1332Leu) (rs199473225)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183056 SCV000235465 pathogenic not provided 2014-07-14 criteria provided, single submitter clinical testing The P1332L mutation in the SCN5A gene has been reported in association with LQTS (Schulze-Bahr E et al., 2004; Ruan Y et al., 2007) as well as observed in three other unrelated individuals tested for LQTS at GeneDx. Schulze-Bahr et al. reported P1332L in a newborn who demonstrated episodes of fetal bradycardia and tachycardia, and an extremely prolonged QT interval. Molecular studies revealed P1332L occurred de novo in the infant, and the mutation was absent in 200 control alleles. Ruan et al. identified P1332L in two unrelated individuals with LQTS who were treated with Mexiletine and demonstrated remarkable shortening of the QT interval. Functional studies demonstrated P1332L is devoid of a sustained sodium current (Ruan Y et al., 2007). P1332L is a non-conservative amino acid change in the S4-S5 linker domain of DIII (Schulze-Bahr E et al., 2004), and multiple other mutations associated with LQTS have been reported in neighboring codons (A1330P, A1330T, S1333Y, I1334V), supporting the functional importance of this region of the protein. Furthermore, P1332L was not observed in approximately 6,000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, P1332L in the SCN5A gene is interpreted as a disease-causing mutation.The variant is found in LQT panel(s).
Invitae RCV000058623 SCV000545005 pathogenic Brugada syndrome 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 1332 of the SCN5A protein (p.Pro1332Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with long QT syndrome (LQTS) or referred for LQTS testing, being reported as de novo in one of these cases (PMID: 14676229, 17698727, 18752142, 23631430). ClinVar contains an entry for this variant (Variation ID: 67844). This variant has been reported to affect SCN5A protein function (PMID: 17698727). For these reasons, this variant has been classified as Pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV001255563 SCV001432043 pathogenic Long QT syndrome 2020-08-03 criteria provided, single submitter clinical testing Variant summary: SCN5A c.3995C>T (p.Pro1332Leu) results in a non-conservative amino acid change located in the Ion transport domain (IPR005821) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251040 control chromosomes (gnomAD). c.3995C>T has been reported in the literature in multiple individuals affected with Long QT Syndrome and Brugada Syndrome (e.g. Ruan_2007, Riuro_2015, Liu_2018, Shimizu_2019). These data indicate that the variant is very likely to be associated with disease. Publications also reported experimental evidence evaluating an impact on protein function, and demonstrated slower inactivation and prominent late Na+ currents (Ruan_2007, Liu_2018). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058623 SCV000090143 not provided Brugada syndrome no assertion provided literature only This variant has been reported as associated with Brugada syndrome in the following publications (PMID:14676229;PMID:15136511;PMID:17698727;PMID:18752142;PMID:20129283). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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