ClinVar Miner

Submissions for variant NM_000719.7(CACNA1C):c.6011G>T (p.Gly2004Val) (rs374991642)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000546112 SCV000627581 likely benign Long QT syndrome 2020-01-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000618390 SCV000737650 uncertain significance Cardiovascular phenotype 2018-02-28 criteria provided, single submitter clinical testing Insufficient evidence
Fulgent Genetics,Fulgent Genetics RCV000763839 SCV000894761 uncertain significance Timothy syndrome; Brugada syndrome 3 2018-10-31 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001255539 SCV001432002 likely benign not specified 2020-08-17 criteria provided, single submitter clinical testing Variant summary: CACNA1C c.6011G>T (p.Gly2004Val) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 7.7e-05 in 246344 control chromosomes, predominantly at a frequency of 0.00015 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 15 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Timothy Syndrome phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.6011G>T in individuals affected with Timothy Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (2x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.

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