SCN5A Variant R1626C Detail

We estimate the penetrance of LQTS for SCN5A R1626C around 43% and the Brugada syndrome penetrance around 10%. SCN5A R1626C was found in a total of 2 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 1 had LQTS. R1626C is present in 1 alleles in gnomAD. R1626C has been functionally characterized in 1 papers. This residue is located in a Non_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 (1 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 R1626C around 43% (2/12) and the Brugada syndrome penetrance around 10% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-7.5 1 -2.99 0.944 5 49
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
30059973 2018 1 1 0 0
LITERATURE, COHORT, AND GNOMAD: - 2 1 1 0 -
VARIANT FEATURES ALONE: - 15 13 1 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.

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)
30059973 2018

R1626C has 71 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 13 L271V,
266 10 L266H,
1569 13 A1569P,
1544 10 T1544P,
270 10 Q270K,
1627 6
1567 9 F1567L,
1624 7 V1624I,
1536 15
1538 8
1566 13
1568 9
1543 11 V1543L, V1543A,
1602 9
1534 13
1542 8
1601 9 L1601H,
1575 14 C1575S,
1600 12
1571 9 F1571C,
1572 13
1564 8
1570 13 I1570V, p.1570_F1571insI, p.I1570dup,
1599 9
1546 12 M1546T,
1545 7
1630 10 I1630R, I1630V,
1626 0 R1626P, R1626H, R1626L, R1626C,
267 11
1603 13 I1603F,
1625 6
1606 12 T1606I,
1560 12 L1560F,
262 14 S262G,
1596 13 F1596C, F1596I,
1628 8
1632 12 R1632L, R1632C, R1632H,
1539 11 C1539F, C1539Y,
1597 10 V1597M,
269 13
1620 11 T1620K, T1620M,
1535 13
1537 11
1565 12 L1565M,
1594 11 F1594S,
264 14
1591 14 W1591X,
1548 12 G1548K, E1548K,
1593 15 I1593M,
1595 10
265 14 A265V,
1619 10 c.4856delC, P1619Q, P1619L,
263 12 V263I,
1629 7 R1629X, R1629Q, R1629G,
1605 12 c.4813+5insTGGG, c.4813+2_4813+5dupTGGG, c.4813+3_4813+6dupGGGT, G1605D, G1605C,
1547 14 V1547L,
1574 13 c.4719C>T, E1574K,
1563 11
1541 6
1592 15
1540 11
1617 12 p.F1617del,
1631 13 G1631D,
268 14 G268S,
1604 13 V1604M, c.4810+3_4810+6dupGGGT,
1622 5
1618 12
1621 10
1598 6 V1598A,
1561 12
1623 6 R1623L, R1623Q, R1623X, c.4867delC,