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

gnomAD frequency: 0.00165  dbSNP: rs61757261

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000114741	SCV000289138	benign	Atrial fibrillation, familial, 6	2024-01-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000780554	SCV000917915	benign	not specified	2021-12-15	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 263016 control chromosomes, predominantly at a frequency of 0.0029 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 92.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPPA causing Atrial Fibrillation phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.190A>C has been reported in the literature in multiple individuals affected with Atrial Fibrillation and Arrythmia, but also in healthy controls (example: Abraham_2010, Ritchie_2012, Disertori_2012, Disertori_2016, Hertz_2014, Hertz_2016, Guelly_2020). Co-occurrences with other pathogenic variants have been reported (SCN5A c.361C>T / p.Arg121Trp, Hertz_2014; KCNH2 c.2587C>T / p.Arg863X, internal sample), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, reporting 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 ClinVar submitters have assessed this variant since 2014: one classified the variant as likely benign and the other as benign. Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV002498490	SCV002808950	likely benign	Atrial fibrillation, familial, 6; Atrial standstill 2	2022-05-16	criteria provided, single submitter	clinical testing
Breakthrough Genomics, Breakthrough Genomics	RCV000857935	SCV005256905	likely benign	not provided		criteria provided, single submitter	not provided
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
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000857935	SCV001972785	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000780554	SCV001978950	benign	not specified		no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000857935	SCV001979887	likely benign	not provided		no assertion criteria provided	clinical testing