Submissions for variant NM_000238.4(KCNH2):c.2900dup (p.Pro968fs)

dbSNP: rs786204101

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168023	SCV000218675	pathogenic	Long QT syndrome	2015-06-25	criteria provided, single submitter	clinical testing	This sequence change has been reported in one individual affected with long QT syndrome (PMID: 18752142) and is not present in population databases. This sequence change duplicates a C nucleotide in exon 12 of the KCNH2 mRNA (c.2900dupC), causing a frameshift at codon 968. This creates a premature translational stop signal (p.Pro968Alafs*151) and is expected to result in an absent or truncated protein product. Truncating sequence changes in KCNH2 are known to be pathogenic (PMID: 10973849, 17576861). In summary, this is a truncating sequence change  which is not reported in population databases, and has been observed in in one individual affected with long QT. For these reasons, this sequence change has been classified as Pathogenic
GeneDx	RCV000182001	SCV000234304	pathogenic	not provided	2016-01-18	criteria provided, single submitter	clinical testing	The c.2900dupC pathogenic variant in the KCNH2 gene has been reported previously in association with LQTS (Berge et al., 2008; Seethala et al., 2015). The c.2900dupC varaint causes a shift in reading frame starting at codon Proline 968, changing it to an Alanine, and creating a premature stop codon at position 151 of the new reading frame, denoted p.Pro968AlafsX151. This pathogenic variant is expected to result in an abnormal protein product. Other frameshift variants in the KCNH2 gene have been reported in HGMD in association with LQTS (Stenson et al., 2014). Furthermore, the c.2900dupC variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project (average read depth 9.0).
deCODE genetics, Amgen	RCV003485546	SCV004022222	pathogenic	Long QT syndrome 2	2023-07-21	no assertion criteria provided	research	The variant NM_000238.4:c.2900dup (chr7:150947670) in KCNH2 was detected in 8 heterozygotes out of 58K WGS Icelanders (MAF= 0,007%). Following imputation in a set of 166K Icelanders (20 imputed heterozygotes) we observed an association with an elongation of the qt interval on ECG using measurements from 80068 individuals (Effect (SD)= 1.18, P= 3.38e-03). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic.