SCN5A Variant M1701I Detail

We estimate the penetrance of LQTS for SCN5A M1701I around 4% and the Brugada syndrome penetrance around 8%. SCN5A M1701I was found in a total of 2 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. M1701I is present in 2 alleles in gnomAD. M1701I has been functionally characterized in 1 papers. This residue is located in a Mild_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 (0 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 M1701I around 4% (0/12) and the Brugada syndrome penetrance around 8% (0/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-3.7 0.766 2.48 0.853 7 1
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
28701297 2017 1 0 0 1 DCM
LITERATURE, COHORT, AND GNOMAD: - 2 2 0 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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.

Functional Data

Peak and late/persistent current are relative to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype.
PubMed ID Year Cell Type Peak Current (%WT) V1/2 Act. (mV) V1/2 Inact. (mV) Late/Persistent Current (%WT)
28701297 2017

M1701I has 68 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
1702 5
387 9
391 12
388 12 I388S,
1698 5 A1698T,
1220 13 G1220E,
1673 10
1675 12
1666 11
1711 14 c.5131delG,
1707 10
1694 10
1704 6 L1704H,
1226 13
1706 10 Q1706H,
1695 13 Q1695X,
1716 14 p.L1716SfsX71,
1688 15
1669 8
1671 11
1668 5 M1668T,
1676 10 M1676I, M1676T,
1692 11
386 13 G386E, G386R,
1219 14 S1219N,
1672 7 S1672Y,
1693 11
1699 7
378 11
331 13
1665 8
379 14
1703 7
1663 14
397 15 I397F, I397V, I397T,
1759 14 S1759C,
1662 14
1709 13 T1709R, T1709M, p.T1709del,
1701 0 M1701I,
1307 15
1228 15 Y1228H, Y1228C, Y1228F,
1223 10 c.3667delG,
1755 12
1697 7
389 14 Y389H, Y389X,
1222 14 p.L1222LfsX7, L1222R,
1227 15
393 13
1674 14 F1674V,
390 8
394 10
1708 10 T1708I,
382 12
1696 9
374 14 W374G,
1705 6
1700 5
1751 14
1677 15
1752 14
1224 12
1670 11
1661 13 G1661R, G1661E,
1691 12
1679 14
398 14
1667 10 V1667I,
1664 11