SCN5A Variant Q1528L Detail

We estimate the penetrance of LQTS for SCN5A Q1528L around 7% and the Brugada syndrome penetrance around 30%. SCN5A Q1528L was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. Q1528L is not present in gnomAD. Q1528L has been functionally characterized in 0 papers. This residue is located in a Mild_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 (2 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 Q1528L around 7% (0/10) and the Brugada syndrome penetrance around 30% (2/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.873 39 5
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: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 13 0 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.

Q1528L has 30 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
1525 10 V1525A, V1525M,
1524 10 I1524T,
1536 14
1531 6
1635 12
1534 12
1522 13
1523 11 D1523N,
1527 6 K1527R,
1639 14 G1639A,
1529 5
1526 8 T1526P,
1532 7 V1532I, V1532F,
1797 15 I1797V,
1800 12
1793 15 M1793K,
1632 15 R1632L, R1632C, R1632H,
1530 8
1796 13
1535 12
1799 15
1638 11 R1638X, R1638Q,
1633 15
1637 15
1636 11
1574 15 E1574K, c.4719C>T,
1533 10 T1533I,
1578 14 c.4732_4733dupAA,
1528 0
1577 15