SCN5A Variant C1539F Detail

We estimate the penetrance of LQTS for SCN5A C1539F around 12% and the Brugada syndrome penetrance around 9%. SCN5A C1539F was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. C1539F is present in 1 alleles in gnomAD. C1539F has been functionally characterized in 0 papers. This residue is located in a Non_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 (1 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 C1539F around 12% (0/11) and the Brugada syndrome penetrance around 9% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-9.39 0.998 1.22 0.84 1 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
LITERATURE, COHORT, AND GNOMAD: - 1 1 0 0 -
VARIANT FEATURES ALONE: - 15 14 0 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.

C1539F has 54 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 12 L266H,
1544 10 T1544P,
1627 10
1567 10 F1567L,
1536 6
1538 4
1531 13
1566 14
1635 13
1568 15
1634 13 L1634P,
1543 7 V1543L, V1543A,
1534 9
1542 6
260 14
1571 11 F1571C,
1564 14
1570 13 p.1570_F1571insI, p.I1570dup, I1570V,
258 13 V258A,
1529 15
1546 10 M1546T,
1545 10
1630 7 I1630V, I1630R,
1532 10 V1532I, V1532F,
1626 11 R1626C, R1626P, R1626L, R1626H,
267 15
1625 15
262 11 S262G,
256 15
1628 11
1632 9 R1632H, R1632L, R1632C,
1539 0 C1539Y, C1539F,
1530 14
255 14
1535 6
1537 6
259 10
1633 8
1591 14 W1591X,
1595 13
265 15 A265V,
1637 14
1636 11
358 14
263 11 V263I,
1629 9 R1629G, R1629X, R1629Q,
1547 14 V1547L,
1574 14 E1574K, c.4719C>T,
1533 10 T1533I,
1563 13
1541 7
1540 5
1631 10 G1631D,
1598 15 V1598A,