ClinVar Miner

Submissions for variant NM_198056.2(SCN5A):c.3988G>A (p.Ala1330Thr) (rs199473224)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000183053 SCV000235462 pathogenic not provided 2018-03-14 criteria provided, single submitter clinical testing The A1330T pathogenic variant in the SCN5A gene has been reported previously in multipleindividuals with LQTS (Van Langen et al., 2003; Smits et al., 2005; Kapa et al., 2009). Smits et al.(2005) identified A1330T in a 14-year-old female with a prolonged QTc interval who died suddenly;subsequently, the variant was shown to segregate with disease in four affected family members. The A1330T variant was not observed in approximately 6,500 individualsof European and African American ancestry in the NHLBI Exome Sequencing Project, nor was itobserved in the Exome Aggregation Consortium (ExAC), indicating it is not a common benign variantin these populations.A1330T is a non-conservative amino acid substitution, which is likely to impact secondary proteinstructure as these residues differ in polarity, charge, size and/or other properties. Moreover, thisvariant affects a highly conserved residue in the DIIIS4-S5 linker which has been shown to beimportant in channel fast inactivation in voltage-gated sodium channels (Smits et al., 2005).Electrophysiology studies demonstrated that A1330T induces a positive shift in the voltagedependenceof steady-state inactivation and accelerates recovery from inactivation likely resulting indelayed repolarization (Smits et al., 2005). Finally, another variant at the same residue (A1330P) hasbeen reported to have occurred de novo in an infant with a prolonged QT interval who died of SIDS(Wedekind et al., 2001), further supporting the functional importance of this region of the protein.In summary, A1330T in the SCN5A gene is interpreted as a pathogenic variant.
Integrated Genetics/Laboratory Corporation of America RCV000589022 SCV000700036 likely pathogenic Cardiovascular phenotype 2016-09-06 criteria provided, single submitter clinical testing Variant summary: The SCN5A c.3988G>A (p.Ala1330Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant is absent in 120776 control chromosomes. This variant has been reported in one LQTS family with co-segregation in 5 affected members (Smits_2005). No additional patient who carries this variant has been reported so far. In vitro study showed this variant shifts the voltage range of I(Na, window) activity to more positive potentials. Here the counter-acting effect of outward K+ current is reduced and may delay AP repolarization, explaining the LQT3 phenotype (Smits_2005). However, the magnitude of the electrophysiological findings reported by the authors does not seem dramatically different from those of the wild-type controls as compared to the other pathogenic variant (p.A1330P) which is known to be associated with LQT3. Nevertheless, the authors interpret their findings as an increased persistent inward current caused by this variant. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic until additional functional studies and co-segregation of this variant in other patients/families with LQT3 are obtained.
Invitae RCV000804115 SCV000944009 pathogenic Brugada syndrome 2019-09-04 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 1330 of the SCN5A protein (p.Ala1330Thr). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with long QT syndrome in a family (PMID: 16039271). ClinVar contains an entry for this variant (Variation ID: 67842). This variant has been reported to affect SCN5A protein function (PMID: 16039271). This variant disrupts the p.Ala1330 amino acid residue in SCN5A. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11535573). This suggests that this residue is clinically-significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058621 SCV000090141 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:12566525;PMID:19841300). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
GenomeConnect, ClinGen RCV000509258 SCV000606948 not provided SCN5A-related disorder no assertion provided phenotyping only GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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