ClinVar Miner

Submissions for variant NM_006172.4(NPPA):c.190A>C (p.Ser64Arg) (rs61757261)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Integrated Genetics/Laboratory Corporation of America RCV000780554 SCV000917915 uncertain significance not specified 2018-05-14 criteria provided, single submitter clinical testing Variant summary: NPPA c.190A>C (p.Ser64Arg) 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 0.0019 in 289492 control chromosomes in the gnomAD database and publications (Abraham_2010, Weeke_2015), including 1 homozygotes. The observed variant frequency is approximately 31.06 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPPA causing Atrial fibrillation phenotype (6.3e-05), suggesting that the variant might be in the benign spectrum. The variant, c.190A>C, has been reported in the literature in individuals affected with Atrial fibrillation and Brugada syndrome, but also in healthy family members and controls (Abraham_2010, Disertori_2012, Disertori_2016, Hertz_2014). Co-occurrences with other pathogenic variant(s) have been reported (GJA5 c.286G>T, A96S), providing supporting evidence for a benign role (Hertz_2014). One publication reports experimental evidence for increased cardiac potassium current associated with this variant (Abraham_2010). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Invitae RCV000114741 SCV000289138 likely benign Atrial fibrillation, familial, 6 2017-09-12 criteria provided, single submitter clinical testing
OMIM RCV000114741 SCV000148624 pathogenic Atrial fibrillation, familial, 6 2010-01-01 no assertion criteria provided literature only

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