ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.221C>T (p.Thr74Met) (rs199473422)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000058097 SCV000234242 likely pathogenic not provided 2015-11-12 criteria provided, single submitter clinical testing p.Thr74Met (ACG>ATG): c.221 C>T in exon 2 of the KCNH2 (aka HERG) gene (NM_000238.2)The Thr74Met mutation in the KCNH2 gene has been reported in at least two unrelated individuals with LQTS and it was absent from at least 2,600 control alleles (Napolitano C et al., 2005; Kapplinger J et al., 2009). Kapa et al. identified Thr74Met in one Caucasian control individual and reported it as a 'rare control'. Nevertheless, the NHLBI ESP Exome Variant Server reports Thr74Met was not observed in approximately 6,000 samples from individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. Mutations at this codon (Thr74Arg, Thr74Pro) and in nearby codons (Pro72Arg, Pro72Gln, Pro72Leu, Ala78Pro) have been reported in association with LQTS, further supporting the functional importance of this codon and this region of the protein.In summary, Thr74Met in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Invitae RCV000807020 SCV000947046 uncertain significance Long QT syndrome 2018-07-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with methionine at codon 74 of the KCNH2 protein (p.Thr74Met). The threonine residue is weakly conserved and there is a moderate physicochemical difference between threonine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with long QT syndrome or referred for long QT syndrome testing (PMID: 16414944, 24606995, 19716085). This variant has also been observed in a healthy control individual (PMID: 22949429). ClinVar contains an entry for this variant (Variation ID: 67377). Experimental studies have shown that this missense change creates a trafficking deficient KCNH2 protein (PMID: 25417810). 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.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058097 SCV000089617 not provided not provided no assertion provided literature only This variant has been reported in the following publications (PMID:16414944;PMID:19716085;PMID:19841300).

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