Submissions for variant NM_000238.4(KCNH2):c.1918T>C (p.Phe640Leu)

dbSNP: rs199473529

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000182036	SCV000234339	pathogenic	not provided	2014-09-23	criteria provided, single submitter	clinical testing	p.Phe640Leu (TTC>CTC): c.1918 T>C in exon 7 of the KCNH2 gene (NM_000238.2). The F640L mutation in the KCNH2 gene has been reported in association with LQTS (Jongbloed et. al., 1999; Kapa et. al., 2009; Giudicessi et. al., 2012). Jongbloed et. al. (1999) initially identified the F640L amino acid substitution (resulting from a different nucleotide substitution, c.1920 C>A) in one Dutch individual of Surinam background diagnosed with LQT2. The F640L mutation (also resulting from a different nucleotide substitution, c.1920 C>A) was subsequently reported as pathogenic in one individual referred for LQTS genetic testing and was absent from 2600 control alleles (Kapa et. al., 2009; Giudicessi et. al., 2012). The F640L mutation is located in the helical transmembrane domain at a residue that is highly conserved across species. Mutations in this same amino acid residue (F640V) and in nearby residues (K638E, K638N, S641F, I642M) have been reported in association with LQTS, further supporting the functional importance of this residue and this region of the protein. Furthermore, the F640L mutation was not observed in approximately 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, F640L in the KCNH2 gene is interpreted as a disease-causing mutation. The variant is found in LQT panel(s).
Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	RCV000678951	SCV000805166	uncertain significance	Long QT syndrome 2	2018-04-25	criteria provided, single submitter	clinical testing