ClinVar Miner

Submissions for variant NM_005477.3(HCN4):c.458A>G (p.Glu153Gly)

gnomAD frequency: 0.00149  dbSNP: rs560874115
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Total submissions: 14
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000723946 SCV000224482 uncertain significance not provided 2018-09-13 criteria provided, single submitter clinical testing
Invitae RCV001082507 SCV000288913 likely benign Brugada syndrome 8 2024-01-29 criteria provided, single submitter clinical testing
GeneDx RCV000723946 SCV000321764 likely benign not provided 2021-05-28 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 29588962, 28341588, 30847666)
Ambry Genetics RCV000618430 SCV000735071 likely benign Cardiovascular phenotype 2018-07-22 criteria provided, single submitter clinical testing This alteration is classified as likely 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.
Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego RCV000852712 SCV000995426 likely benign Primary dilated cardiomyopathy; Cardiomyopathy 2019-06-11 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001117433 SCV001275619 uncertain significance Sick sinus syndrome 2, autosomal dominant 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago RCV003224176 SCV003920028 uncertain significance Sick sinus syndrome 2, autosomal dominant; Brugada syndrome 8; Epilepsy, idiopathic generalized, susceptibility to, 18 2021-03-30 criteria provided, single submitter clinical testing HCN4 NM_005477.2 exon 1 p.Glu153Gly (c.458A>G): This variant has been reported in the literature in one individual with genearlized epilepsy and in one individual with unspecified cardiac arrhythmia (Becker 2017 PMID:29588962, Proost 2017 PMID:28341588). This variant did not segregate with disease in at least four affected family members with epilepsy (Becker 2017 PMID:29588962). This variant is present in 0.1% (31/14734) of European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/variant/15-73660154-T-C). This variant is present in ClinVar (Variation ID:180370). This variant amino acid Glycine (Gly) is present in several bird and fish species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. However, an in vitro functional study using voltage clamp anaylsis does predict that this variant will impact the protein by causing a hyperpolarizing shift in activation and reduced current amplitudes (Becker 2017 PMID:29588962). However, this study may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
CeGaT Center for Human Genetics Tuebingen RCV000723946 SCV004132801 benign not provided 2023-03-01 criteria provided, single submitter clinical testing HCN4: PP3, BS1, BS2
Blueprint Genetics RCV000157245 SCV000206972 uncertain significance Brugada syndrome 2014-10-28 no assertion criteria provided clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000723946 SCV001742089 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics, Academic Medical Center RCV000723946 SCV001920653 likely benign not provided no assertion criteria provided clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000723946 SCV001931500 likely benign not provided no assertion criteria provided clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ RCV000723946 SCV001958798 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000723946 SCV001971864 likely benign not provided no assertion criteria provided clinical testing

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