SCN5A Variant V1624I Detail

We estimate the penetrance of LQTS for SCN5A V1624I around 16% and the Brugada syndrome penetrance around 10%. SCN5A V1624I was found in a total of 2 carriers in 1 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. V1624I is present in 2 alleles in gnomAD. V1624I has been functionally characterized in 1 papers. This residue is located in a Mild_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 (1 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 V1624I around 16% (1/12) and the Brugada syndrome penetrance around 10% (1/12).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
-0.89 0.179 3.03 0.764 15 30
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
29544605 2018 1 0 0 1 SIDS
LITERATURE, COHORT, AND GNOMAD: - 2 2 0 0 -
VARIANT FEATURES ALONE: - 15 13 1 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.

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)
29544605 2018

V1624I has 56 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 8 L271V,
266 9 L266H,
1544 15 T1544P,
270 9 Q270K,
1627 5
396 14 V396A, V396L,
1624 0 V1624I,
355 15 F355I, F355C,
1538 13
391 12
388 14 I388S,
1602 13
1542 11
1601 11 L1601H,
260 15
1600 15
1564 14
1599 14
1546 14 M1546T,
1545 10
1630 11 I1630V, I1630R,
1626 7 R1626H, R1626L, R1626C, R1626P,
267 7
1625 4
262 14 S262G,
399 15
272 12
273 14
1628 6
1632 14 R1632H, R1632C, R1632L,
1597 11 V1597M,
392 11
389 12 Y389X, Y389H,
269 12
1620 7 T1620M, T1620K,
395 11
393 15
1594 10 F1594S,
264 10
1591 13 W1591X,
1548 14 E1548K, G1548K,
1593 14 I1593M,
1595 13
265 12 A265V,
1619 9 c.4856delC, P1619Q, P1619L,
263 10 V263I,
1629 10 R1629X, R1629G, R1629Q,
1541 12
1617 11 p.F1617del,
1631 13 G1631D,
268 10 G268S,
1622 7
1618 10
1621 5
1598 9 V1598A,
1623 6 R1623L, R1623Q, R1623X, c.4867delC,