SCN5A Variant P1619L Detail

We estimate the penetrance of LQTS for SCN5A P1619L around 18% and the Brugada syndrome penetrance around 23%. SCN5A P1619L was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. P1619L is present in 1 alleles in gnomAD. P1619L has been functionally characterized in 0 papers. This residue is located in a Non_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 P1619L around 18% (1/11) and the Brugada syndrome penetrance around 23% (2/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-9.25 0.977 -0.86 0.905 31 16
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 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.

P1619L has 51 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 9 L271V,
266 14 L266H,
270 9 Q270K,
1627 12
385 15 A385T,
1624 9 V1624I,
388 15 I388S,
1602 11
1601 10 L1601H,
1609 13 S1609L, S1609W,
1557 14 I1557V,
1608 14
1613 9 Q1613H, Q1613L,
1600 14
1615 13 Y1615X,
1612 13
1564 13
1599 15
1545 12
1626 10 R1626L, R1626P, R1626C, R1626H,
267 12
1603 14 I1603F,
1625 10
1606 12 T1606I,
1560 15 L1560F,
1610 11 D1610G,
272 13
274 15 G274C,
273 12
1628 15
1597 14 V1597M,
389 13 Y389H, Y389X,
269 13
1620 4 T1620K, T1620M,
275 13 N275K,
1614 10
1548 13 G1548K, E1548K,
1619 0 P1619L, c.4856delC, P1619Q,
1605 10 G1605D, G1605C, c.4813+5insTGGG, c.4813+3_4813+6dupGGGT, c.4813+2_4813+5dupTGGG,
1611 15 I1611V,
1541 15
1616 11
1617 6 p.F1617del,
268 13 G268S,
1604 11 c.4810+3_4810+6dupGGGT, V1604M,
1622 6
1618 4
1621 7
1598 12 V1598A,
1561 14
1623 5 R1623L, R1623Q, c.4867delC, R1623X,