Submissions for variant NM_000335.5(SCN5A):c.1700T>A (p.Leu567Gln)

gnomAD frequency: 0.00001  dbSNP: rs199473124

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000619630	SCV000738223	uncertain significance	Cardiovascular phenotype	2020-08-12	criteria provided, single submitter	clinical testing	The c.1700T>A (p.L567Q) alteration is located in exon 12 (coding exon 11) of the SCN5A gene. This alteration results from a T to A substitution at nucleotide position 1700, causing the leucine (L) at amino acid position 567 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003137597	SCV000813706	uncertain significance	not provided	2025-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 567 of the SCN5A protein (p.Leu567Gln). This variant is present in population databases (rs199473124, gnomAD no frequency). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 10711933, 11076825, 29915097). ClinVar contains an entry for this variant (Variation ID: 67678). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Experimental studies have shown that this missense change affects SCN5A function (PMID: 11123251, 24573164). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Diagnostics, LLC DBA Color Health	RCV001842291	SCV000911572	uncertain significance	Cardiac arrhythmia	2023-05-01	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 567 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant may cause a reduction in peak current density (PMID: 24573164). Another functional study has shown that this variant may play a role in modulating inactivation of the cardiac sodium channel (PMID: 11123251). This variant has been reported in a family affected with Brugada syndrome and multiple incidences of sudden infant death (PMID: 10711933, 11901046), and in an asymptomatic individual with a family history of Brugada syndrome (PMID: 24963427). This variant has also been reported in an individual affected with sudden unexplained death (PMID: 29915097) and in multiple individuals affected with ischemic stroke (PMID: 36973604). This variant has been identified in 2/249034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics	RCV001329631	SCV001521123	uncertain significance	Atrial fibrillation, familial, 10	2020-02-04	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001797620	SCV002041843	uncertain significance	not specified	2021-11-15	criteria provided, single submitter	clinical testing	Variant summary: SCN5A c.1700T>A (p.Leu567Gln) results in a non-conservative amino acid change located in the Voltage-gated Na+ ion channel, cytoplasmic domain (IPR024583) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249034 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1700T>A has been reported in the literature in one individual with ST-segment elevation in leads V1-V3 and a suspected diagnosis of Brugada syndrome (Priori_2000). The pedigree as reported for this individual was non-informative due to insufficient genotyped affected family members as all were deceased (due to sudden death). Additionally, at-least three unaffected relatives with this variant were reported. At-least one additional case report of an asymptomatic pregnancy with this variant and a family history of sudden cardiac deaths has been reported (Giambanco_2014). The variant has also been reported with conflicting interpretations of pathogenicity (P and VUS respectively) in two cases within the setting of sudden unexplained death in the young (SUDY) (Shanks_2018, Pearman_2020). Lastly, one recent report has classified this variant as a VUS citing caution when extrapolating functional testing to the likelihood of variant pathogenicity (Rochtus_2020). Since the ascertained penetrance of Brugada Syndrome due to this variant appears to be lower than expected, no conclusions can be drawn from these data. At least two publications report experimental evidence evaluating an impact on protein channel function, however, does not allow convincing conclusions about the variant effect (Wan_2001 and Hoshi_2014). Subsequent reports evaluating all published literature have concluded that the relationship between in vitro assessment of channel function and Brugada syndrome clinical phenotype is weak and there exists no relationship between any aspect of channel function and conduction abnormalities/sudden cardiac death or spontaneous Brugada ECG pattern (Pearman_2020). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Revvity Omics, Revvity	RCV003137597	SCV003821335	uncertain significance	not provided	2021-12-01	criteria provided, single submitter	clinical testing
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV003989313	SCV004806675	uncertain significance	Brugada syndrome 1	2024-03-26	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001842291	SCV004831384	uncertain significance	Cardiac arrhythmia	2024-04-16	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with glutamine at codon 567 of the SCN5A protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). An in-vitro functional study has shown that this variant may cause a reduction in peak current density (PMID: 24573164). Another functional study has shown that this variant may play a role in modulating inactivation of the cardiac sodium channel (PMID: 11123251). This variant has been reported in a family affected with Brugada syndrome and multiple incidences of sudden infant death (PMID: 10711933, 11901046), and in an asymptomatic individual with a family history of Brugada syndrome (PMID: 24963427). This variant has also been reported in an individual affected with sudden unexplained death (PMID: 29915097) and in multiple individuals affected with ischemic stroke (PMID: 36973604). This variant has been identified in 2/249034 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust	RCV000058442	SCV000089962	not provided	Brugada syndrome		no assertion provided	literature only	This variant has been reported as associated with Brugada syndrome in the following publications (PMID:10711933;PMID:11901046;PMID:11076825;PMID:11123251). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000845516	SCV000987619	likely pathogenic	Long QT syndrome		flagged submission	clinical testing
Centre for Addiction & Mental Health, Centre for Addiction & Mental Health	RCV004698467	SCV005200250	uncertain significance	Autism		no assertion criteria provided	research	Gene not previously associated with disease; independent supportng evidence needed