ClinVar Miner

Submissions for variant NM_000218.2(KCNQ1):c.1726G>A (p.Val576Ile) (rs750409379)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000767090 SCV000234377 uncertain significance not provided 2018-10-30 criteria provided, single submitter clinical testing The V576I variant in the KCNQ1 gene has been reported previously in one individual with LQTS (Mullaly J et al., 2013). In addition, V576I has been reported in one individual with a swimming-induced syncopal event and a paternal family history of sudden unexplained death who also harbors the R594P mutation in the KCNQ1 gene (Giudicessi J et al., 2013). Segregation analysis in this family showed that the V576I variant was inherited from the asymptomatic mother and that the origin of the R594P mutation is unknown as the father was unavailable for testing (Giudeicessi et al., 2013). The V576I variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Furthermore, missense mutations in nearby residues (S571L, F573L, R583G, R583C, R583H) have been reported in the Human Gene Mutation Database in association with LQTS (Stenson P et al., 2014), supporting the functional importance of this region of the protein. Nevertheless, the V576I variant is a conservative amino acid substitution that occurs at a position that is very poorly conserved across species, with Isoleucine present at this residue in greater than 10 rodent species. Consequently, in silico analysis predicts this variant likely does not alter the protein structure/function.Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000182074 SCV000270311 likely benign not specified 2015-08-13 criteria provided, single submitter clinical testing p.Val576Ile in exon 14 of KCNQ1: This variant is not expected to have clinical significance due to a lack of conservation across species, including mammals. Of note, 13 mammals have an Ile at this position despite high nearby amino acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identified in 5/65838 European chromosomes by the Exome Aggregation Consortium (ExAC, Although this variant has been reported in 2 individuals with LQTS (1 with intact hearing who carried a second likely pathogenic variant) (Mullally 2013, Giudicessi 2013), based on the lack of conservation at this position, this variant is likely benign.

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