ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.627GCC[6] (p.Pro214dup)

dbSNP: rs746833511
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000462970 SCV000551861 uncertain significance Atrial septal defect 7 2023-11-28 criteria provided, single submitter clinical testing This variant, c.639_641dup, results in the insertion of 1 amino acid(s) of the NKX2-5 protein (p.Pro214dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs777382725, gnomAD 0.07%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with NKX2-5-related conditions (PMID: 34374102). This variant is also known as p.P213dup. ClinVar contains an entry for this variant (Variation ID: 410968). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000617268 SCV000737747 likely benign Cardiovascular phenotype 2019-11-12 criteria provided, single submitter clinical testing This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786394 SCV000925203 uncertain significance not provided 2017-09-28 no assertion criteria provided provider interpretation Found in a 14 yo female with incomplete RBBB on EKG and a history of two syncopal episodes during exercise. Her echocardiogram and cardiac MRI were read as normal. p.Pro214dup (c.639_641dupGCC) in the NKX2.5 gene (NM_004387.3) Chromosome location 5:172659912 -- / GGC Based on the information reviewed below, we classify this as a Variant of Uncertain Significance, Probably Benign, concluding that there is not sufficient evidence for its pathogenicity to warrant using it for predictive genetic testing. It may be a benign ethnicity-specific variant that is more common in individuals with Latino ancestry like our patient. The NKX2.5 gene is associated with atrial septal defect with or without atrioventricular conduction defects (MedGen UID: 400040), among other things. Our patient has not shown signs of this phenotype. This variant has not previously been reported in the literature in association with disease, according to the Invitae report. It is present, however, in population databases at an allele count that is higher than expected for a pathogenic variant. This is an in-frame insertion of a Proline amino acid amid a string of 7 Prolines. This variant was reported in at least 36 individuals in the gnomAD database, which includes variant calls on ~140,000 individuals of European, African, Latino, South Asian, Ashkenazi, and East Asian descent. Specifically, the variant was observed in 23 out of 15,976 Latinos (for the highest allele frequency: 0.07%), 6 South Asians, 4 non-Finnish Europeans, 2 Africans, and 1 “Other” ancestry individual. The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. The curators made an effort to exclude individuals with severe pediatric diseases.

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