rs199473070
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP2PP3_Strong
The NM_000335.5(SCN5A):āc.635T>Cā(p.Leu212Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,634 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L212V) has been classified as Uncertain significance.
Frequency
Consequence
NM_000335.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SCN5A | NM_000335.5 | c.635T>C | p.Leu212Pro | missense_variant | 6/28 | ENST00000423572.7 | |
SCN5A | NM_001099404.2 | c.703+164T>C | intron_variant | ENST00000413689.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SCN5A | ENST00000423572.7 | c.635T>C | p.Leu212Pro | missense_variant | 6/28 | 1 | NM_000335.5 | A1 | |
SCN5A | ENST00000413689.6 | c.703+164T>C | intron_variant | 5 | NM_001099404.2 | P4 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457634Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 724664
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Atrial standstill 1, digenic Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2005 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 17, 2018 | Experimental studies have shown that this missense change alters sodium channel kinetics (PMID: 16188595, 20539757, 20384651). 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. This variant has been observed in an individual affected with sick sinus syndrome (PMID: 16188595) and in several individuals referred for long QT syndrome or Brugada syndrome testing (PMID: 19716085, 25904541). ClinVar contains an entry for this variant (Variation ID: 68030). This variant is not present in population databases (ExAC no frequency). This sequence change replaces leucine with proline at codon 212 of the SCN5A protein (p.Leu212Pro). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and proline. - |
Congenital long QT syndrome Other:1
not provided, no classification provided | literature only | Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust | - | This variant has been reported as associated with Long QT syndrome in the following publications (PMID:16188595;PMID:19716085;PMID:20539757). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at