3-38605976-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3
The NM_001099404.2(SCN5A):āc.1313T>Cā(p.Met438Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000497 in 1,611,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M438L) 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 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.1313T>C | p.Met438Thr | missense_variant | 10/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.1313T>C | p.Met438Thr | missense_variant | 10/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.1313T>C | p.Met438Thr | missense_variant | 10/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.1313T>C | p.Met438Thr | missense_variant | 10/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000404 AC: 1AN: 247794Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134432
GnomAD4 exome AF: 0.00000480 AC: 7AN: 1458904Hom.: 0 Cov.: 31 AF XY: 0.00000414 AC XY: 3AN XY: 725404
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152096Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74296
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | May 20, 2019 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C65"). This variant has not been reported in the literature in individuals with SCN5A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with threonine at codon 438 of the SCN5A protein (p.Met438Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 21, 2019 | The p.M438T variant (also known as c.1313T>C), located in coding exon 9 of the SCN5A gene, results from a T to C substitution at nucleotide position 1313. The methionine at codon 438 is replaced by threonine, an amino acid with similar properties, and is located in the DI/DII interdomain linker region. Another variant affecting this codon (p.M438L, c.1312A>T) has been reported in a Brugada syndrome cohort; however clinical details were limited (Robyns T et al. Ann Noninvasive Electrocardiol, 2018 09;23:e12548). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at