rs730880202
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP2PP3_Moderate
The NM_001099404.2(SCN5A):c.328G>A(p.Ala110Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,461,662 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A110D) has been classified as Uncertain significance.
Frequency
Consequence
NM_001099404.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_001099404.2 | c.328G>A | p.Ala110Thr | missense_variant | 3/28 | ENST00000413689.6 | |
SCN5A | NM_000335.5 | c.328G>A | p.Ala110Thr | missense_variant | 3/28 | ENST00000423572.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000413689.6 | c.328G>A | p.Ala110Thr | missense_variant | 3/28 | 5 | NM_001099404.2 | P4 | |
SCN5A | ENST00000423572.7 | c.328G>A | p.Ala110Thr | missense_variant | 3/28 | 1 | NM_000335.5 | A1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152188Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000160 AC: 4AN: 249516Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135334
GnomAD4 exome AF: 0.0000281 AC: 41AN: 1461662Hom.: 0 Cov.: 30 AF XY: 0.0000303 AC XY: 22AN XY: 727134
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cardiac arrhythmia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 13, 2023 | This missense variant replaces alanine with threonine at codon 110 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having long QT syndrome (PMID 23174487, 23631430, 26159999). This variant has been identified in 4/249516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Jun 08, 2023 | This missense variant replaces alanine with threonine at codon 110 of the SCN5A protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with or suspected of having long QT syndrome (PMID 23174487, 23631430, 26159999). This variant has been identified in 4/249516 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 10, 2022 | This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 110 of the SCN5A protein (p.Ala110Thr). This variant is present in population databases (rs730880202, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of long QT syndrome (PMID: 23174487, 23631430, 26159999, 32048431). ClinVar contains an entry for this variant (Variation ID: 180510). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2017 | A variant of uncertain significance has been identified in the SCN5A gene. The A110T variant has been reported in association with Long QT Syndrome (LQTS) in one patient who also harbored additional variants (Mullally et al., 2013). This variant has also been reported in one individual with a normal QT interval (Ghouse et al., 2015). Nevertheless, the A110T variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A110T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Finally, this substitution occurs at a position that is conserved across species and, in silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Blueprint Genetics | Nov 27, 2014 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2023 | The p.A110T variant (also known as c.328G>A), located in coding exon 2 of the SCN5A gene, results from a G to A substitution at nucleotide position 328. The alanine at codon 110 is replaced by threonine, an amino acid with similar properties. This variant has been detected in pts from cohorts reported to have long QT syndrome (LQTS) or who were referred for LQTS genetic testing; however, in one instance, this variant was indicated as co-occurring with nonsense and frameshift variants in the KCNQ1 gene, and the reported cases may overlap (Lieve KV et al. Genet Test Mol Biomarkers, 2013 Jul;17:553-61). (Mullally J et al. Heart Rhythm, 2013 Mar;10:378-82). This variant has also been detected in an individual with normal QTc interval, and in a cohort not selected for the presence of arrhythmia or cardiovascular disease (Ghouse J et al. Eur Heart J, 2015 Oct;36:2523-9; Diebold I et al. Hum Mutat, 2020 05;41:1025-1032). This amino acid position is highly 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