Submissions for variant NM_005477.3(HCN4):c.546C>G (p.Pro182=)

gnomAD frequency: 0.00122  dbSNP: rs571671463

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV001081299	SCV000288915	benign	Brugada syndrome 8	2024-02-01	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000274839	SCV000337462	benign	not specified	2015-11-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000274839	SCV000513213	benign	not specified	2015-10-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics	RCV000619534	SCV000737453	benign	Cardiovascular phenotype	2015-11-02	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Athena Diagnostics Inc	RCV000711895	SCV000842306	benign	not provided	2018-02-19	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000274839	SCV004222959	benign	not specified	2023-11-20	criteria provided, single submitter	clinical testing	Variant summary: HCN4 c.546C>G alters a conserved nucleotide resulting in a synonymous change. Consensus agreement among computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0045 in 216826 control chromosomes, predominantly at a frequency of 0.028 within the Latino subpopulation in the gnomAD database, including 14 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 2688-fold of the estimated maximal expected allele frequency for a pathogenic variant in HCN4 causing Sick Sinus Syndrome 2 phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.546C>G in individuals affected with Sick Sinus Syndrome 2 and no experimental evidence demonstrating its impact on protein function have been reported. Five submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign.