ClinVar Miner

Submissions for variant NM_004387.4(NKX2-5):c.491C>A (p.Ser164Ter)

dbSNP: rs1554093487
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000621937 SCV000737031 pathogenic Cardiovascular phenotype 2017-07-17 criteria provided, single submitter clinical testing The p.S164* pathogenic mutation (also known as c.491C>A), located in coding exon 2 of the NKX2-5 gene, results from a C to A substitution at nucleotide position 491. This changes the amino acid from a serine to a stop codon within coding exon 2. This alteration is expected to result in loss of function by premature protein truncation. Truncating variants in the NKX2-5 gene are well-reported as disease-causing in individuals with septal defects and atrioventricular block (Schott JJ et al. Science, 1998 Jul;281:108-11; Benson DW et al. J. Clin. Invest., 1999 Dec;104:1567-73). As such, this alteration is interpreted as a disease-causing mutation.
Invitae RCV003767784 SCV004641527 pathogenic Atrial septal defect 7 2023-09-17 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the NKX2-5 protein in which other variant(s) (p.Ala262Argfs*32) have been determined to be pathogenic (PMID: 22920929). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. ClinVar contains an entry for this variant (Variation ID: 519074). This premature translational stop signal has been observed in individual(s) with congenital heart disease (PMID: 32369864). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Ser164*) in the NKX2-5 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 161 amino acid(s) of the NKX2-5 protein.

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