SCN5A Variant M642I Detail

We estimate the penetrance of LQTS for SCN5A M642I around 11% and the Brugada syndrome penetrance around 15%. SCN5A M642I was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M642I is not present in gnomAD. M642I has been functionally characterized in 0 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a Mild_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (1 diagnosed with Brugada syndrome) and 5 individuals for LQTS (0 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A M642I around 11% (0/10) and the Brugada syndrome penetrance around 15% (1/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.457 17 13
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance Density is our previously published method to calculate the average BrS/LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT3 BrS1 Other Other Disease
LITERATURE, COHORT, AND GNOMAD: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 1 - -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

M642I has 31 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
627 15 P627L,
628 14 P628R,
629 14 D629Y,
630 13 T630M,
631 13 c.1890+5G>A, c.1890G>A, p.T631VfsX101,
632 12 T632M,
633 11
634 11 S634W, S634L,
635 10
636 9 E636K,
637 8 P637L,
638 8 G638D,
639 7 G639A, G639R,
640 5 P640S, P640L, P640A,
641 4
642 0
643 4
644 5
645 7
646 8 c.1936delC, p.Q646RfsX5,
647 8 A647S, A647D, A647V,
648 9 P648L,
649 10 C649Y, C649R,
650 11
651 11 D651H, c.1950_1953delAGAT,
652 12 G652D, G652S,
653 13
654 13 E654K, E654X , E654D, E654Q,
655 14 E655K,
656 14 P656L,
657 15