SCN5A Variant R1629G Detail

We estimate the penetrance of LQTS for SCN5A R1629G around 7% and the Brugada syndrome penetrance around 48%. SCN5A R1629G was found in a total of 2 carriers in 2 papers and/or in gnomAD: 2 had Brugada syndrome, 0 had LQTS. R1629G is not present in gnomAD. R1629G has been functionally characterized in 2 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 (3 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 R1629G around 7% (0/12) and the Brugada syndrome penetrance around 48% (5/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-6.48 1 -4.41 0.96 51 10
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
19843921 2009 1 0 1 0
27232914 2016 1 0 1 0
LITERATURE, COHORT, AND GNOMAD: - 2 0 0 2 -
VARIANT FEATURES ALONE: - 15 12 0 3 - -
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)
19843921 2009
27232914 2016

R1629G has 65 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
266 13 L266H,
1569 13 A1569P,
1544 14 T1544P,
1627 7
1586 12
1567 11 F1567L,
1624 10 V1624I,
1536 13
1538 5
1531 12
1566 15
1635 11
1568 11
1587 15 F1587V,
1634 13 L1634P,
1543 14 V1543A, V1543L,
1602 12
1534 9
1542 9
1601 12 L1601H,
1575 11 C1575S,
1600 13
1571 8 F1571C,
1572 12
1564 13
1570 12 p.1570_F1571insI, I1570V, p.I1570dup,
1599 9
1545 12
1630 6 I1630V, I1630R,
1532 14 V1532I, V1532F,
1626 7 R1626P, R1626H, R1626C, R1626L,
267 14
1625 7
262 15 S262G,
1596 11 F1596C, F1596I,
1628 6
1589 12
1632 5 R1632H, R1632C, R1632L,
1539 9 C1539F, C1539Y,
1597 9 V1597M,
1530 13
1573 13
1535 8
1537 9
1594 7 F1594S,
259 13
1633 10
1591 7 W1591X,
1593 10 I1593M,
1595 5
1636 13
263 12 V263I,
1629 0 R1629X, R1629G, R1629Q,
1574 9 c.4719C>T, E1574K,
1533 13 T1533I,
1541 8
1592 9
1578 11 c.4732_4733dupAA,
1540 12
1631 8 G1631D,
1590 10
1622 11
1621 14
1598 7 V1598A,
1623 13 R1623L, R1623Q, c.4867delC, R1623X,