Submissions for variant NM_000238.4(KCNH2):c.214C>T (p.Pro72Ser)

dbSNP: rs794728411

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000181936	SCV000234239	pathogenic	not provided	2014-04-12	criteria provided, single submitter	clinical testing	p.Pro72Ser (CCG>TCG): c.214 C>T in exon 2 of the KCNH2 gene (NM_000238.2)The P72S mutation in the KCNH2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. However, different missense mutations at the same residue (P72Q, P72R, P72L) have been reported in association with LQTS (Splawski et al., 2000; Crotti et al., 2008; Kapplinger et al., 2009). Additionally, mutations in nearby residues (G71R, G71E, T74R, T74M, T74P) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. The P72S variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. This substitution occurs at a position that is mostly conserved across species. Furthermore, the P72S mutation was not observed inapproximately 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, P72S in the KCNH2 gene is interpreted as a likely disease-causing mutation. The variant is found in LQT panel(s).
Mayo Clinic Laboratories, Mayo Clinic	RCV000181936	SCV002103219	likely pathogenic	not provided	2021-09-10	criteria provided, single submitter	clinical testing	PP3, PM1, PM2, PM5
Labcorp Genetics (formerly Invitae), Labcorp	RCV002516850	SCV003335603	uncertain significance	Long QT syndrome	2023-07-08	criteria provided, single submitter	clinical testing	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. This variant disrupts the p.Pro72 amino acid residue in KCNH2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10973849, 19716085, 21440677; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 200564). This variant has not been reported in the literature in individuals affected with KCNH2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 72 of the KCNH2 protein (p.Pro72Ser).