Submissions for variant NM_000218.3(KCNQ1):c.1686G>T (p.Arg562Ser)

dbSNP: rs794728535

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182214	SCV000234517	pathogenic	not provided	2012-12-03	criteria provided, single submitter	clinical testing	p.Arg562Ser (AGG>AGT):c.1686 G>T in exon 14 of the KCNQ1 gene (NM_000218.2). The Arg562Ser mutation in KCNQ1 has been reported previously in association with LQTS. Andrsova I et al. (2012) reported Arg562Ser in one patient with LQTS and did not identify the mutation in 180 reference alleles. Barsheshet A et al. (2012) also identified this mutation in 4 individuals diagnosed with LQTS. Arg562Ser results in a non-conservative amino acid replacement of a positively charged Arginine residue with a neutral, polar Serine residue at a residue that is highly conserved across species throughout evolution. In addition, a mutation in the same codon (Arg562Met) and in surrounding codons (Arg555Cys, Arh555His, Arg555Ser, Ser566Phe, Ser566Pro, Ser566Trp, Ile567Ser, Ile567Thr) have also been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein. Furthermore, the NHLBI ESP Exome Variant Server reports Arg562Ser was not observed in approximately 5,400 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Therefore, the presence of Arg562Ser in the KCNQ1 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Labcorp Genetics (formerly Invitae), Labcorp	RCV002517776	SCV003439775	uncertain significance	Long QT syndrome	2022-07-22	criteria provided, single submitter	clinical testing	Experimental studies have shown that this missense change affects KCNQ1 function (PMID: 30170673). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 200855). This missense change has been observed in individuals with prolonged QT intervals in the homozygous and heterozygous state (PMID: 22456477, 22727609, 30170673; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 562 of the KCNQ1 protein (p.Arg562Ser). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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.