ClinVar Miner

Submissions for variant NM_181798.1(KCNQ1):c.449C>G (p.Ser150Trp) (rs199472730)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000046141 SCV000074154 likely pathogenic Long QT syndrome 2019-10-02 criteria provided, single submitter clinical testing This sequence change replaces serine with tryptophan at codon 277 of the KCNQ1 protein (p.Ser277Trp). The serine residue is highly conserved and there is a large physicochemical difference between serine and tryptophan. This variant is not present in population databases (rs199472730, ExAC no frequency). This variant has been reported in several individuals affected with long QT syndrome (PMID: 16414944, 23130128). ClinVar contains an entry for this variant (Variation ID: 53115). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. A different missense substitution at this codon (p.Ser277Leu) has been determined to be pathogenic (PMID: 12442276, 21241880, 21895724). This suggests that the serine residue is critical for KCNQ1 protein function and that other missense substitutions at this position may also be pathogenic. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
GeneDx RCV000182308 SCV000234611 pathogenic not provided 2012-01-16 criteria provided, single submitter clinical testing This missense change is denoted Ser277Trp (aka S277W) at the protein level and c.830 C>G at the cDNA level. The Ser277Trp mutation in the KCNQ1 gene has been reported previously in association with LQTS, and this mutation was absent from 800 control alleles (Napolitano C et al., 2005). The NHLBI ESP Exome Variant Server reports Ser277Trp was not observed in approximately 5,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. In addition, functional studies of a similar missense mutation (Ser277Leu) reported this mutation suppresses normal KCNQ1 channel function (Aidery P et al., 2011). Ser277Trp results in a non-conservative amino acid substitution of a neutral, polar Serine with a non-polar Tryptophan at a residue that is conserved across species. Furthermore, different missense mutations at the same codon (Ser277Leu, Ser277Pro), as well as mutations in nearby codons (Phe275Ser,Trp278His) have also been reported in association with LQTS, further supporting the functional importance of this region of the protein. The variant is found in LQT panel(s).
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000057774 SCV000089293 not provided Congenital long QT syndrome no assertion provided literature only This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16414944). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.

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