SCN5A Variant R1623L Detail

We estimate the penetrance of LQTS for SCN5A R1623L around 55% and the Brugada syndrome penetrance around 19%. SCN5A R1623L was found in a total of 3 carriers in 4 papers and/or in gnomAD: 0 had Brugada syndrome, 3 had LQTS. R1623L is not present in gnomAD. R1623L has been functionally characterized in 4 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 (2 diagnosed with Brugada syndrome) and 5 individuals for LQTS (1 with LQTS). These data combined with observations of carriers lead us to estimate the LQTS penetrance for SCN5A R1623L around 55% (4/13) and the Brugada syndrome penetrance around 19% (2/13).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-6.17 0.154 -3.65 0.92 29 39
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
10973849 2000 1 1 0 0
15840476 2005 1 1 0 0
27566755 2016 3 3 0 0
19716085 2009 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 3 0 3 0 -
VARIANT FEATURES ALONE: - 15 12 1 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)
19716085 2009
10973849 2000
15840476 2005
27566755 2016

R1623L has 62 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 7 L271V,
266 9 L266H,
1544 12 T1544P,
270 5 Q270K,
1627 7
1567 14 F1567L,
1624 6 V1624I,
355 13 F355I, F355C,
1549 14
1538 14
1568 14
356 15 D356N,
1543 14 V1543L, V1543A,
1602 12
1542 11
1601 11 L1601H,
1557 14 I1557V,
1613 14 Q1613H, Q1613L,
1564 11
1599 14
1546 12 M1546T,
1545 7
1630 14 I1630V, I1630R,
1626 6 R1626H, R1626L, R1626C, R1626P,
267 8
1550 14
1625 8
1606 14 T1606I,
1560 12 L1560F,
262 15 S262G,
272 11
274 14 G274C,
273 10
1628 11
1597 13 V1597M,
392 13
389 13 Y389X, Y389H,
269 9
1620 5 T1620M, T1620K,
1565 15 L1565M,
275 13 N275K,
1594 15 F1594S,
264 13
1548 10 E1548K, G1548K,
265 12 A265V,
1619 5 c.4856delC, P1619Q, P1619L,
358 14
263 12 V263I,
1629 13 R1629X, R1629G, R1629Q,
1605 12 c.4813+5insTGGG, G1605D, c.4813+3_4813+6dupGGGT, c.4813+2_4813+5dupTGGG, G1605C,
1547 13 V1547L,
1563 14
1541 11
1617 10 p.F1617del,
268 10 G268S,
1604 14 c.4810+3_4810+6dupGGGT, V1604M,
1622 6
1618 8
1621 7
1598 11 V1598A,
1561 13
1623 0 R1623L, R1623Q, R1623X, c.4867delC,