ClinVar Miner

Submissions for variant NM_000335.4(SCN5A):c.1714_1715delinsTT (p.Ala572Phe) (rs730880211)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000726236 SCV000235565 likely benign not provided 2021-06-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19862833, 18071069, 21109022, 23631430, 30847666)
Invitae RCV001080833 SCV000291782 likely benign Brugada syndrome 2020-11-18 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000726236 SCV000343113 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618061 SCV000736007 likely benign Cardiovascular phenotype 2019-02-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Color Health, Inc RCV001191832 SCV001359745 uncertain significance Arrhythmia 2020-11-25 criteria provided, single submitter clinical testing This missense variant replaces alanine with phenylalanine at codon 572 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 experimental functional study has shown that this variant does not impact sodium currents and voltage-dependent activation, although it results in a shorter recovery time from inactivation (PMID: 18071069). This variant has been reported in an individual affected with cardiomyopathy (PMID: 18071069) and in an individual referred for long QT syndrome testing (PMID: 23631430). This variant has also been identified in 67/280362 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Alanine at this codon position is poorly conserved through evolution, although phenylalanine is not observed in any mammalian species. Different missense variants occurring at the same codon (Ala572Val, Ala572Asp, Ala572Ser) are common benign polymorphisms. 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.
Blueprint Genetics RCV000157498 SCV000207243 uncertain significance Primary familial hypertrophic cardiomyopathy 2014-03-19 no assertion criteria provided clinical testing

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