Submissions for variant NM_000218.3(KCNQ1):c.827C>T (p.Ser276Phe)

gnomAD frequency: 0.00001  dbSNP: rs794728514

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182122	SCV000234425	likely pathogenic	not provided	2012-05-25	criteria provided, single submitter	clinical testing	p.Ser276Phe (TCC>TTC): c.827 C>T in exon 6 of the KCNQ1 gene (NM_000218.2). The Ser276Phe variant in the KCNQ1 gene has not been reported previously as a disease-causing mutation or as a benign polymorphism, to our knowledge. Ser276Phe results in a non-conservative amino acid substitution of a neutral, polar Serine with a non-polar Phenylalanine at a residue that is conserved across species. In silico analysis predicts Ser276Phe is probably damaging to the protein structure/function. In addition, mutations in nearby residues (Phe275Ser, Ser277Leu, Ser277Pro, Ser277Trp) have been reported in association with LQTS, supporting the functional importance of this region of the protein. The Ser276Phe 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. In summary, while the clinical significance of Ser276Phe in the KCNQ1 gene is currently unknown, the evidence suggests it is a good candidate for a disease-causing mutation. The variant is found in LQT panel(s).
Ambry Genetics	RCV002408794	SCV002675730	uncertain significance	Cardiovascular phenotype	2021-07-13	criteria provided, single submitter	clinical testing	The p.S276F variant (also known as c.827C>T), located in coding exon 6 of the KCNQ1 gene, results from a C to T substitution at nucleotide position 827. The serine at codon 276 is replaced by phenylalanine, an amino acid with highly dissimilar properties, and is located in the transmembrane S5 domain. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV003996710	SCV004829844	uncertain significance	Long QT syndrome	2023-08-08	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 276 of the KCNQ1 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with KCNQ1-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.