3-38606764-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP2
The NM_001099404.2(SCN5A):c.1045G>A(p.Asp349Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D349E) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1045G>A | p.Asp349Asn | missense_variant | 9/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1045G>A | p.Asp349Asn | missense_variant | 9/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1045G>A | p.Asp349Asn | missense_variant | 9/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1045G>A | p.Asp349Asn | missense_variant | 9/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000121 AC: 3AN: 248950Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 135042
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461496Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727030
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152206Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74358
ClinVar
Submissions by phenotype
not provided Pathogenic:1Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 20, 2022 | PS3_supporting, PS4_supporting - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 349 of the SCN5A protein (p.Asp349Asn). This variant is present in population databases (rs779687673, gnomAD 0.009%). This missense change has been observed in individuals with Brugada syndrome (PMID: 23200271, 24721456, 29709101, 31737537, 33221895, 36220970). ClinVar contains an entry for this variant (Variation ID: 229230). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 32533946) did not meet the statistical confidence thresholds required to predict the impact of this variant on SCN5A function. Experimental studies have shown that this missense change affects SCN5A function (PMID: 32533946). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 14, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 18, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 16, 2016 | The p.Asp349Asn variant in SCN5A has been identified in one Caucasian individual with Brugada syndrome and as a compound heterozygote in one individual with sic k sinus syndrome (Kodma 2013, Savastano 2013). It has been identified in 2/1156 4 Latino chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org; dbSNP rs779687673). Computational prediction tools and conservat ion analysis suggest that the p.Asp349Asn variant may not impact the protein, th ough this information is not predictive enough to rule out pathogenicity. In sum mary, the clinical significance of the p.Asp349Asn variant is uncertain. - |
Brugada syndrome 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | May 15, 2018 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Aug 14, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at