SCN5A Variant p.M903CfsX29 Detail

We estimate the penetrance of LQTS for SCN5A p.M903CfsX29 around 6% and the Brugada syndrome penetrance around 18%. SCN5A p.M903CfsX29 was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. p.M903CfsX29 is present in 1 alleles in gnomAD. p.M903CfsX29 has been functionally characterized in 0 papers. This residue is located in a Hotspot region for Brugada syndrome and a Non_Hotspot region for LQTS. In silico predictions, functional data (if available), and location in structure are equivalent to phenotyping 10 individuals for Brugada syndrome (2 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 p.M903CfsX29 around 6% (0/11) and the Brugada syndrome penetrance around 18% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA None 23 6
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: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 2 - -
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.

p.M903CfsX29 has 69 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
364 11
891 12 I891T, I891N,
880 15
890 11 I890T,
901 8 E901K, S901L,
919 5
862 15
363 8
896 15 C896S,
348 15 P348A,
895 14 L895F,
360 10
894 9 I894M,
372 10
361 14
904 5 W904X,
366 11
887 14
365 14
864 14
376 14 R376C, R376H,
354 14
897 12 G897R, G897E,
924 14 V924I,
909 11
857 13 G857D,
902 5
349 12 D349N,
373 12
881 12
898 11
893 11 R893C, R893H,
921 12
922 11 V922I,
860 14 p.L860fsx89,
362 13
911 10 G911E,
920 8
900 5
918 9
917 9 L917R, L917V,
865 13
913 10
916 6
912 9 Q912R,
347 15
906 6
351 12 G351D, G351V, G351C, G351S,
910 10 S910L,
350 9 H350Q,
903 0 p.M903CfsX29,
367 9 R367L, R367C, R367H,
359 13 A359T, p.A359PfsX12,
853 14
370 12 T370M,
877 14
879 14 W879R,
923 11
905 7
352 9 Y352C,
915 6 C915R,
368 15
899 6
377 14
908 10
914 10
861 11 c.2582_2583delTT, p.F861WfsX90,
353 11 T353I,
907 5