Variant detail

SCN5Ap.F1617del

c.4850del · residue 1617 · p.F → del
Technical Plain language
HGVS annotation

ClinVar-style identity and transcript context

ClinVar-style HGVS
NM_000335.5(SCN5A):c.4850del (p.F1617del)
HGVSc
c.4850del
cDNA change
c.4850del
RefSeq transcript
NM_000335.5
Ensembl transcript
ENST00000333535.9
Protein HGVS
p.F1617del
Genomic coordinate
Chr3 38593013
ClinVar annotation
Not annotated in local ClinVar field
BrS1 penetrance Low risk
13% 90% credible interval 7–21%
0%20%50%100%

Well-established · n=51 6 observed BrS1 carriers · 1.87 hypothetical affected and 8.13 hypothetical unaffected

LQT3 penetrance High risk
55% 90% credible interval 44–65%
0%20%50%100%

Well-established · n=51 29 observed LQT3 carriers · 1.53 hypothetical affected and 3.47 hypothetical unaffected

One-sentence summary

Roughly 1 in 2 people who carry p.F1617del are estimated to eventually be diagnosed with Long QT type 3 — high penetrance, with well-supported evidence from 51 carriers. The residue lies in a Mild_Hotspot region for BrS1 and a Mild_Hotspot region for LQT3.

Executive summary

Sources used for interpretation

The BrS1 and LQT3 penetrance estimates combine observed carrier counts with phenotype-specific feature-based model starting points. Other rows summarize supporting annotations for interpretation; not every row is a direct input to the model.

Estimatemodel output Observedmeasured in people/assays Model inputassumed, not observed Predictedcomputational Externalthird-party
EstimateModel-based penetrance estimatesBrS1 13% · LQT3 55%
Model inputHypothetical observationsBrS1 1.87/8.13 · LQT3 1.53/3.47
ObservedObserved carriers (literature + cohorts)51 · Well-established
ObservedPopulation observations (gnomAD v4)5 alleles
PredictedIn silico predictorsREVEL · PolyPhen-2 · PROVEAN · BLAST-PSSM
ObservedFunctional / electrophysiologyNA
PredictedStructural contextMild_Hotspot
ExternalClinVar classificationNot annotated
ExternalAutomated ACMG reviewNot a classification
ExternalExternal databasesClinVar · gnomAD · UniProt

Evidence

Carriers observed
51
6 BrS1 · 29 LQT3 · 16 unaffected
Model prior: BrS1 1.87 hypothetical affected / 8.13 hypothetical unaffected; LQT3 1.53 hypothetical affected / 3.47 hypothetical unaffected
Well-established
Functional data
NA
12 published electrophysiology studies
Predictors and density
REVEL —range 0-1
PolyPhen-2 NArange 0-1
BrS1 density Sparse region0.202range 0-1
LQT3 density Sparse region0.392range 0-1
PROVEAN NAcutoff <= -2.5
BLAST-PSSM NAlower = less tolerated
Range labels show the expected scale or cutoff. Calls are rough orientation from published cutoffs (hover a row) — not a clinical classification.

Automated ACMG/AMP review prompts

Generated from available data — not a clinical classification
PS3met · strong
Functional studies show damaging effect
PM1review
Hotspot or high BrS1/LQT3 density
PM2not met
Absent / extremely rare in population databases
PP3not met
Multiple computational predictors support deleterious
BS1not met
Allele frequency too high for disorder
BP4met · supporting
Computational predictors suggest no impact

Reported carrier data

Paper / cohort Carriers LQT3 / BrS1 Unaffected Other observations Variant context
Year 2000 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2010 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2015 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2014 · clinical carrier record
4 1 LQT3 3 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2016 · clinical carrier record
6 4 LQT3 2 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2017 · clinical carrier record
41 25 LQT3
5 BrS1 		8 3 other phenotype
CCD lots of overlaps
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2016 · clinical carrier record
5 5 LQT3 0 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2006 · clinical carrier record
1 0 LQT3
1 BrS1 		0 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2009 · clinical carrier record
1 1 LQT3 0 Not separately annotated
Variant p.F1617del
Residue 1617
Curated carrier-count row
Year 2018 · clinical carrier record
4 4 LQT3 0 Not separately annotated
Variant p.F1617del
Residue *
Curated carrier-count row
gnomAD population observations (v4) 5 0 LQT3
0 BrS1		 5 Population observations; not known affected cases. gnomAD v4 allele count.
Hypothetical observations from model prior (not observed patients) 5 LQT3 prior;
10 BrS1 prior		 1.53 hypothetical LQT3 affected;
1.87 hypothetical BrS1 affected		 3.47 hypothetical LQT3 unaffected;
8.13 hypothetical BrS1 unaffected		 Phenotype-specific feature-based pseudo-counts added before observed carriers. Model input; not literature or gnomAD evidence.
Combined literature, cohort, and gnomAD 51 29 LQT3
6 BrS1		 16 Combined totals used in the dual penetrance estimates. Curated carrier totals for this variant.

Model starting point. The BrS1 model starts with 1.87 hypothetical affected and 8.13 hypothetical unaffected observations; the LQT3 model starts with 1.53 hypothetical affected and 3.47 hypothetical unaffected observations. Each then updates that starting point with the real carrier counts above. As observed carrier counts grow, these feature-based starting points have less influence.

Functional studies · researcher detail
PMIDYearCellPeak (%WT)V½ act (mV)V½ inact (mV)Late (%WT)
10973849 2000 ————
20541041 2010 ————
25205533 2015 ————
25236808 2014 ————
26669661 2016 ————
28782696 2017 ————
15665061 2005 ————
29017927 2017 ————
27566755 2016 ————
17081365 2006 ————
19716085 2009 ————
30059973 2018 ————
Structural neighbours · researcher detail

Residues within 15 Å of p.F1617del; observed variants link to their detail pages.

NeighbourDistance (Å)Observed variants
27114.6 L271V,
27014.8 Q270K,
162714.9
162411.2 V1624I,
156814.3
16028.7
16015.4 L1601H,
160910.6 S1609W, S1609L,
160810.3
16137.6 Q1613L, Q1613H, Q1613H,
16009.8
16159.8 Y1615X,
161211.1
156414.5
159911.7
162611.6 R1626C, R1626H, R1626P, R1626L
16039.9 I1603F,
162510.0
160610.4 T1606I,
16109.0 D1610G,
159614.1 F1596I, F1596C,
159710.4 V1597M,
16208.3 T1620K, T1620M,
16149.0
16196.3 P1619Q, P1619L, c.4856delC,
16057.0 c.4813+2_4813+5dupTGGG, c.4813+3_4813+6dupGGGT, c.4813+5insTGGG, G1605C, G1605D,
161111.6 I1611V,
16165.7
160712.2
16170.0 p.F1617del,
16046.2 c.4810+3_4810+6dupGGGT, V1604M,
16226.3
16183.7
16217.0
159810.2 V1598A,
162310.0 c.4867delC, R1623X, R1623Q, R1623L,
View this variant elsewhere
ClinVar → gnomAD → UniProt →