ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.355G>T (p.Ala119Ser) (rs137852684)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000171007 SCV000223570 likely benign not specified 2017-12-13 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000230156 SCV000288517 benign Atrial septal defect 7 with or without atrioventricular conduction defects 2019-12-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000620259 SCV000735072 likely benign Cardiovascular phenotype 2019-01-04 criteria provided, single submitter clinical testing Other strong data supporting benign classification;In silico models in agreement (benign)
Integrated Genetics/Laboratory Corporation of America RCV000171007 SCV000917901 benign not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: NKX2-5 c.355G>T (p.Ala119Ser) results in a 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 0.00097 in 259522 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 194.2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NKX2-5 causing Congenital Heart Disease phenotype (5e-06), strongly suggesting that the variant is benign. The variant, c.355G>T has been reported in the literature in individuals affected with Congenital Heart Disease, and the same publication reports experimental evidence evaluating an impact on protein function that showed variant behaves equal to wildtype NKX2-5 (vanEngelen_2012). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
OMIM RCV000009584 SCV000029802 pathogenic Hypothyroidism, congenital, nongoitrous, 5 2006-04-01 no assertion criteria provided literature only

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