Submissions for variant NM_000335.5(SCN5A):c.998+5G>T

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Neuberg Centre For Genomic Medicine, NCGM	RCV003340961	SCV004047855	uncertain significance	Dilated cardiomyopathy 1E		criteria provided, single submitter	clinical testing	The splice site c.998+5G>T variant has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.998+5G>T variant is novel (not in any individuals) in gnomAD exomes and 1000 Genomes. This variant has not been reported to the ClinVar database. The nucleotide c.998+5G>T in SCN5A is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain significance (VUS).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004786922	SCV005399137	uncertain significance	Brugada syndrome 1	2022-03-31	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3A. Following criteria are met: 0103 - Loss of function and gain of function are both known mechanisms of disease in this gene. Loss of function is usually associated with Brugada syndrome 1 (MIM#601144) and sick sinus syndrome 1 (SSS; MIM#608567), whereas gain of function is usually associated with long QT syndrome-3 (LQTS; MIM#603830). Dilated cardiomyopathy 1E (DCM; MIM#601154) can be caused by variants with either a loss or gain of function mechanism (PMID: 29798782). (I) 0108 - This gene is associated with both recessive and dominant disease. Most conditions associated with this gene are dominantly inherited; however SSS is caused by biallelic variants (OMIM). (I) 0212 - Non-canonical splice site variant without proven consequence on splicing (no functional evidence available). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - An alternative nucleotide change at the same nucleotide position is present in gnomAD (v2) (58 heterozygotes, 0 homozygotes). (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0708 - Another splice variant comparable to the one identified in this case has conflicting previous evidence for pathogenicity. c.998+5G>A has been reported as likely benign, but more commonly as a VUS (ClinVar, LOVD). It has also been observed in an individual with LQTS, who had an additional variant in the KCNH2 gene (PMID: 23631430). (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign