SCN5A Variant V1547L Detail

We estimate the penetrance of LQTS for SCN5A V1547L around 4% and the Brugada syndrome penetrance around 16%. SCN5A V1547L was found in a total of 1 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. V1547L is present in 1 alleles in gnomAD. V1547L 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 (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 V1547L around 4% (0/11) and the Brugada syndrome penetrance around 16% (1/11).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-2.67 0.286 1.47 0.781 22 3
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.

V1547L has 47 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 10 L266H,
1544 6 T1544P,
270 10 Q270K,
360 15
1627 14
1567 14 F1567L,
1552 9 Q1552R, Q1552L,
355 15 F355C, F355I,
1549 7
1556 8
356 11 D356N,
1543 7 V1543A, V1543L,
1558 13
1542 10
1557 11 I1557V,
361 13
1562 14
1564 12
1546 6 M1546T,
1545 7
1626 14 R1626L, R1626C, R1626H, R1626P,
267 14
1550 12
1560 7 L1560F,
262 13 S262G,
357 9
362 15
273 11
1559 10 I1559V,
1553 11 S1553R,
1539 14 C1539Y, C1539F,
269 9
1548 5 G1548K, E1548K,
1555 13 E1555K,
265 12 A265V,
358 9
1551 12 D1551Y, D1551N,
263 15 V263I,
359 12 p.A359PfsX12, A359T,
1547 0 V1547L,
1563 11
1541 11
1554 13
1540 11
268 13 G268S,
1561 12
1623 13 R1623Q, R1623X, c.4867delC, R1623L,