SCN5A Variant L1988P Detail

We estimate the penetrance of LQTS for SCN5A L1988P around 4% and the Brugada syndrome penetrance around 6%. SCN5A L1988P was found in a total of 0 carriers in 0 papers and/or in gnomAD: 0 had Brugada syndrome, 0 had LQTS. L1988P is not present in gnomAD. L1988P 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 (0 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 L1988P around 4% (0/10) and the Brugada syndrome penetrance around 6% (0/10).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density BrS (%) Penetrance Density LQT3 (%)
NA NA NA 0.294 1 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: - 0 0 0 0 -
VARIANT FEATURES ALONE: - 15 15 0 0 - -
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.

L1988P has 31 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
1973 15 F1973L,
1974 14
1975 14 P1975T,
1976 13 S1976C,
1977 13 Y1977N,
1978 12
1979 11
1980 11 V1980F,
1981 10
1982 9 R1982T,
1983 8 A1983G, A1983V,
1984 8 T1984I,
1985 7 S1985R,
1986 5 D1986G, D1986N,
1987 4 N1987K,
1988 0 L1988R,
1989 4
1990 5 V1990L,
1991 7 R1991Q, R1991W,
1992 8 G1992A,
1993 8
1994 9
1995 10 Y1995X,
1996 11 S1996R, S1996N,
1997 11 H1997R,
1998 12
1999 13
2000 13 D2000Y,
2001 14
2002 14 A2002T,
2003 15 D2003N,