ClinVar Miner

Submissions for variant NM_172056.2(KCNH2):c.215C>A (p.Pro72Gln) (rs199473421)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463612 SCV000543425 pathogenic Long QT syndrome 2020-10-03 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 72 of the KCNH2 protein (p.Pro72Gln). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with long QT syndrome (PMID: 10973849, 21440677, Invitae) and in individuals referred for long QT testing (PMID: 19716085). ClinVar contains an entry for this variant (Variation ID: 67368). Experimental studies have shown that this missense change causes a defect in protein trafficking and decreases dimerization (PMID: 25417810). Other missense substitutions at this codon (p.Pro72Arg and p.Pro72Thr) have been reported in individuals affected with long QT syndrome (PMID: 20960620, 26496715). For these reasons, this variant has been classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588659 SCV000696011 pathogenic Cardiovascular phenotype 2016-02-22 criteria provided, single submitter clinical testing Variant summary: KCNH2 c.215C>A affects a conserved nucleotide, resulting in amino acid change from Pro to Gln. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index), and functional studies indicate P72Q to have deficient trafficking (Anderson_2014). This variant was not found in 70930 control chromosomes, but has been reported in multiple LQT2 pts. In addition, multiple clinical laboratories classified this variant as pathogenic. Taken together, this variant was classified as a disease variant/pathogenic.
Ambry Genetics RCV000588659 SCV000737850 pathogenic Cardiovascular phenotype 2020-01-09 criteria provided, single submitter clinical testing The p.P72Q pathogenic mutation (also known as c.215C>A), located in coding exon 2 of the KCNH2 gene, results from a C to A substitution at nucleotide position 215. The proline at codon 72 is replaced by glutamine, an amino acid with similar properties. This alteration has been previously detected in numerous individuals from long QT syndrome cohorts (Moss AJ et al. Circulation. 2002;105:794-9; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303; Itoh H et al. Eur. J. Hum. Genet. 2016;24:1160-6; GeneDx pers. comm.; Ambry internal data). One study reported this alteration to result in abnormal protein trafficking (Anderson CL et al. Nat Commun. 2014;5:5535). Two likely pathogenic variants, p.P72R and p.P72L, have been described in the same codon (Crotti L et al. Hum. Genet. 2008;123:537-55; Kapplinger JD et al. Heart Rhythm. 2009;6:1297-303). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV001258077 SCV001434910 likely pathogenic Long QT syndrome 2 2019-12-13 criteria provided, single submitter clinical testing The KCNH2 c.215C>A gene variant results in an amino acid change from a proline to a glutamine at position 72 in the encoded protein (p.Pro72Gln). This variant is absent from general population databases (gnomAD). This variant has been previously reported in individuals with long QT syndrome (PMID: 11854117, 20486126, 21440677, 10973849, 19716085). Experimental studies suggest this variant results in a deleterious effect on protein trafficking (PMID: 25417810). In addition, other variants at the same codon (p.Pro72Arg and p.Pro72Leu) have been previously reported in individuals with long QT syndrome (PMID: 19716085, 25417810, 23158531). Therefore, this c.215C>A variant in the KCNH2 gene is classified as likely pathogenic.
Cardiovascular Biomedical Research Unit,Royal Brompton & Harefield NHS Foundation Trust RCV000058088 SCV000089608 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:10973849;PMID:11854117;PMID:19716085). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory.
Stanford Center for Inherited Cardiovascular Disease, Stanford University RCV000786141 SCV000924809 likely pathogenic not provided 2015-11-12 no assertion criteria provided provider interpretation

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