Submissions for variant NM_005477.3(HCN4):c.2275G>A (p.Val759Ile)

gnomAD frequency: 0.00258  dbSNP: rs62641689

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Biesecker Lab/Clinical Genomics Section, National Institutes of Health	RCV000170931	SCV000050772	likely benign	not provided	2013-06-24	criteria provided, single submitter	research
GeneDx	RCV000170931	SCV000223490	benign	not provided	2019-05-30	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 30452770, 25467552, 25145517, 23623143, 21615589, 26179811, 30578647, 31043699, 33095298)
Eurofins Ntd Llc (ga)	RCV000185511	SCV000232682	benign	not specified	2015-07-23	criteria provided, single submitter	clinical testing
Scripps Translational Science Institute, Scripps Health and The Scripps Research Institute	RCV000204998	SCV000262544	uncertain significance	Sudden cardiac death	2023-12-04	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV001084342	SCV000288901	benign	Brugada syndrome 8	2025-02-03	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000185511	SCV000539274	likely benign	not specified	2016-04-25	criteria provided, single submitter	clinical testing	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ExAC: 0.5% (358/65892) Europeans, 3 homozygotes
Ambry Genetics	RCV000617204	SCV000735059	likely benign	Cardiovascular phenotype	2021-11-09	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, 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	RCV000170931	SCV001144127	benign	not provided	2019-04-04	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001120898	SCV001279418	benign	Sick sinus syndrome 2, autosomal dominant	2018-03-29	criteria provided, single submitter	clinical testing	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	RCV000185511	SCV001433479	benign	not specified	2020-01-23	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000185511	SCV003844913	benign	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: HCN4 c.2275G>A (p.Val759Ile) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0032 in 243780 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 303 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 benign. To our knowledge, no experimental evidence demonstrating its impact on protein function have been reported. Nine ClinVar submitters (evaluation after 2014) cite this variant as benign (n=6), likely benign (n=2) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as benign.
CeGaT Center for Human Genetics Tuebingen	RCV000170931	SCV004132796	likely benign	not provided	2024-09-01	criteria provided, single submitter	clinical testing	HCN4: BP4, BS2
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000170931	SCV004563097	likely benign	not provided	2023-09-06	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000170931	SCV001741521	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000185511	SCV001917812	benign	not specified		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV000170931	SCV001930346	likely benign	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000185511	SCV001958622	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000170931	SCV001968334	likely benign	not provided		no assertion criteria provided	clinical testing