ClinVar Miner

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

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000463612 SCV000543425 pathogenic Long QT syndrome 2019-02-25 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.
Integrated Genetics/Laboratory Corporation of America 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 likely pathogenic Cardiovascular phenotype 2019-02-14 criteria provided, single submitter clinical testing Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;Rarity in general population databases (dbsnp, esp, 1000 genomes);Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
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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