KCNH2 Variant M844V

Summary of observed carriers, functional annotations, and structural context for KCNH2 M844V. Data combine curated literature, international cohorts, and gnomAD observations.

Estimated LQT2 penetrance

6%

90% CI: 0.5% – 25.5%

0/15 effective observations

Total carriers

5

0 LQT2 · 1 unaffected

Functional studies

0

Publications with functional data

M844V is present in 5 alleles in gnomAD. This residue resides in a Mild_Hotspot region for LQT2.

We have tested the trafficking efficiency of this variant: 94% of WT with a standard error of 18%. In our analysis we used SE < 20% as 'high quality'. Approximately below 50% of WT is considered PS3 moderate and below 30% is PS3 strong.

Variant features alone are equivalent to phenotyping 0 individuals with LQT2 and 10 unaffected individuals.

In silico predictors

Variant-level computational predictors.
PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density LQT2 (%)
-3.289 0.392 1 0.818 25

PROVEAN scores below -2 suggest deleterious impact. REVEL scores above 0.5–0.75 are often interpreted as likely pathogenic. PolyPhen-2 scores above 0.85 are typically pathogenic. BLAST-PSSM reflects evolutionary conservation; more negative values indicate rarer substitutions. Penetrance density summarises neighbouring residue risk (Kroncke et al. 2019).

Reported carrier data

Observed carriers by publication or cohort.
Source Year Carriers Unaffected LQT2 Other Disease
Literature, cohort, and gnomAD – 5 1 0 –
Variant features alone – 10 10 0 –

Totals may differ from individual publications due to duplicate patients removed during curation.

Nearby variants

Neighbouring residues within 15 Ångström provide structural context. Variants listed in the right-most column have been observed clinically or in gnomAD. Note that some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15Å window.

Previously observed variants near M844V.
Neighbour residue Distance (Å) Observed variants
844 0 M844V,
845 5
843 5
841 6 V841L, V841L,
775 6
815 6
842 7
840 7 E840Q,
846 8 P846T, P846S,
817 8
816 8 G816V,
750 9 C750X,
814 9
753 10 A753S,
839 10
773 10
774 10 D774Y, D774X,
749 10
848 10
849 10
838 11 L838R,
776 11 L776I, L776P,
847 11
777 11
754 11
818 12 S818A, S818W, S818L,
757 12
747 12
835 12 R835W, R835fsX, R835Q,
837 12 D837N, D837Y, D837G,
813 13
812 13 Y812S,
772 13
751 13 L751V,
850 14 D850N,
836 14
852 14
746 14 A746S, A746X,
752 14 R752W, R752Q, R752P,
836 14
756 14 M756V,
807 14 E807X,
863 15 R863X, R863P
778 15 A778T,
755 15
853 15 W853X,