ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000114741 SCV000289138 benign Atrial fibrillation, familial, 6 2020-12-04 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780554 SCV000917915 likely benign not specified 2020-11-02 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 0.002 in 294420 control chromosomes, including 1 homozygote. However, in certain subpopulations, e.g. in Bulgarian and Ashkenazy Jewish control individuals the variant occurs with a frequency of 0.0072 and 0.0056 respectively, and these frequencies are approximately 200-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPPA causing Atrial Fibrillation (AF) phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism. c.190A>C has been reported in the literature in individuals affected with Atrial fibrillation and Brugada syndrome, but was also found in healthy family members and unrelated controls (Abraham_2010, Ritchie_2012, Disertori_2012, Disertori_2016, Hertz_2014). Co-occurrences with other (potentially) pathogenic variants have been reported (SCN5A c.361C>T / p.Arg121Trp, Hertz_2014; KCNH2 c.2587C>T / p.Arg863X, in an Internal LCA sample), providing supporting evidence for a benign role. At least one publication reported experimental evidence for an increased potassium current associated with this variant (Abraham_2010). However, a case-control study reported that the variant was relatively common among non-AF controls, which suggested that it may not be causative i.e. the monogenic cause of AF, though it might be associated with very low penetrance or contribute in some as yet undefined fashion to AF susceptibility (Weeke_2015). Two other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as benign (1x) / likely benign (1x). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000857935 SCV001147151 likely benign not provided 2017-05-01 criteria provided, single submitter clinical testing
OMIM RCV000114741 SCV000148624 pathogenic Atrial fibrillation, familial, 6 2010-01-01 no assertion criteria provided literature only
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000857935 SCV001931165 likely benign not provided no assertion criteria provided clinical testing

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