Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
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VIP Variant in SCN5A
H558R was observed with a minor allelic frequency of 9.2% among Asians, 29% among blacks, 20.4% among whites and 23.1% among Hispanics [Article:15851227]. H558R was identified in both drug associated long QT patients (aLQTS) and controls. The frequency of this common nonsynonymous coding region polymorphism was no different between aLQTS patients and control subjects: 24% versus 19% [Article:11997281]. H558R has been reported to modulate a nearby mutation T512I that leads to an enhanced inactivation and conduction disease [Article:12569159]. When H558R was present with Q1077 (which is a splicing variant which makes up 35% of the transcript in human heart) , sodium current was profoundly reduced despite normal trafficking to the cell surface [Article:14500339].
Note: The SCN5A gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
| Key Publications: | |
|---|---|
| Phenotype |
H558R modulates T512I that leads to an enhanced inactivation and conduction disease
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Appendix
2. SCN5A:H558R
| Genomic Variant & GenBank ID: | 38,585,424 T>C on NT_022517 |
|---|---|
| mRNA Variant & GenBank ID: | 1867 A>G on NM_000335 (transcript variant 2); 1867 A>G on NM_198056 (transcript variant 1) |
| Protein Variant & GenBank ID: | 558 His>Arg on NP_000326; 558 His>Arg on NP_932173 (the two sequences are for the two wild-type splice variants) |
| GoldenPath Position: | chr3:38620424 (hg18) |
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): | NA15367 (PA126721270 ) |
| DNA Source Containing Heterozygous Reference Allele(Coriell Lines): | NA15369 (PA126721271) |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines) | NA15216 (PA126721225) |
Publications related to rs1805124 at chr3:38645420: 4
| Spectrum and prevalence of cardiac sodium channel variants among black, white, Asian, and Hispanic individuals: implications for arrhythmogenic susceptibility and Brugada/long QT syndrome genetic testing. Heart rhythm : the official journal of the Heart Rhythm Society. 2004. Ackerman Michael J, et al. [Article:15851227@PubMed] | |
| A ubiquitous splice variant and a common polymorphism affect heterologous expression of recombinant human SCN5A heart sodium channels. Circulation research. 2003. Makielski Jonathan C, et al. [Article:14500339@PubMed] | |
| A common SCN5A polymorphism modulates the biophysical effects of an SCN5A mutation. The Journal of clinical investigation. 2003. Viswanathan Prakash C, et al. [Article:12569159@PubMed] | |
| Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes. Circulation. 2002. Yang Ping, et al. [Article:11997281@PubMed] |
Cross-References
- UCSC Golden Path:
- chr3:38645420
- dbSNP:
- rs1805124
- ALFRED:
- SI273304T
- HapMap:
- rs1805124
Platform Availability
- Illumina