SCN5A Variant T1620K Detail

We estimate the penetrance of LQTS for SCN5A T1620K around 63% and the Brugada syndrome penetrance around 17%. SCN5A T1620K was found in a total of 3 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 3 had LQTS. T1620K is not present in gnomAD. T1620K has been functionally characterized in 2 papers. This residue is located in a Mild_Hotspot region for Brugada syndrome and a 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 (2 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A T1620K around 63% (5/13) and the Brugada syndrome penetrance around 17% (2/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-5.35 0.978 -1.94 0.938 28 53
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
18065446 2008 4 3 0 1 CCD
LITERATURE, COHORT, AND GNOMAD: - 3 0 3 0 -
VARIANT FEATURES ALONE: - 15 11 2 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.

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)
18065446 2008 HEK -5 9.5
21552533 2011 HEK 94 -4.5 -10.9 155

T1620K has 47 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
271 6 L271V,
266 12 L266H,
270 8 Q270K,
1627 11
385 12 A385T,
1624 7 V1624I,
355 14 F355I, F355C,
391 12
388 11 I388S,
1602 14
1601 11 L1601H,
1613 12 Q1613H, Q1613L,
1615 15 Y1615X,
384 15 S384T,
329 14
386 13 G386E, G386R,
1545 12
1626 11 R1626L, R1626P, R1626C, R1626H,
267 10
1625 9
1610 15 D1610G,
272 10
274 14 G274C,
273 12
1628 13
1597 14 V1597M,
392 12
389 10 Y389H, Y389X,
269 12
1620 0 T1620K, T1620M,
395 15
275 12 N275K,
264 14
1614 11
1548 14 G1548K, E1548K,
265 15 A265V,
1619 4 P1619L, c.4856delC, P1619Q,
1605 13 G1605D, G1605C, c.4813+5insTGGG, c.4813+3_4813+6dupGGGT, c.4813+2_4813+5dupTGGG,
1616 13
1617 8 p.F1617del,
268 11 G268S,
1604 14 c.4810+3_4810+6dupGGGT, V1604M,
1622 7
1618 5
1621 4
1598 13 V1598A,
1623 5 R1623L, R1623Q, c.4867delC, R1623X,