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MYH6 c.2161

From SNPedia
Associated with sick sinus syndrome in the Icelandic population.
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ReferenceGRCh37 37.1/132

Icelanders with two copies of the rare T allele at SNP in the MYH6 gene, also known as c.2161, have an increased risk of sick sinus syndrome (SSS), also known as sinus node dysfunction. No rs# has yet been assigned to this location. SSS is a group of disorders that affect heart rhythm.

MYH6 c.2161C>T was discovered in a GWAS published in March 2011 [PMID 21378987]. The discovery phase included 792 Icelandic cases with 37,592 Icelandic controls. The SNPs with the strongest associations with SSS were rs2231801, rs28730774 and 14-22399934. Since rs28730774 was the most significant SNP on the HumanOmni1-Quad chip (p = 1.6E-11; OR = 3.49; minor allele frequency = 0.01), it was studied further.

In the second phase of the study, 7 chip-typed Icelandic cases (4 with the rs28730774 SNP) and 80 chip-typed Icelandic controls were subjected to whole genome sequencing. In this analysis, the MYH6 c.2161C>T variant had the strongest association with SSS. The mutation is located in exon 18 of the MYH6 gene and leads to an arginine to tryptophan amino acid alteration at amino acid 721.

In a follow-up validation study, the odds-ratio was calculated as OR = 12.95 with a p-value = 3.8E-5. No homozygotes were identified. Additionally, 184 Danish, 94 Dutch and 1498 US controls were compared to 135 US SSS cases, and no carriers of MYH6 c.2161C>T were found. The lifetime risk of being diagnosed with sick sinus syndrome was reported to be around 6% for non-carriers of c.2161C>T but approximately 50% for carriers of this (c.2161C>T) variant.

alpha-MyHC is also associated with a 4.16-beat per minute decrease in heart rate (p=0.0019).

The minor allele (T) results in a missense mutation in the MYH6 gene, encoding the alpha-myosin heavy chain (alpha-MyHC) protein. This protein is a fast ATPase present mainly in atrial tissue. The p.Arg721Trp variant resides in part of the converter domain of alpha-MyHC and is important for amplifying structural rearrangements of myosin during contraction. This variant has been predicted to result in structural alterations [PMID 21378987].

As of May 2011, no frequency data are available.

SNP 28730774
PubMedID [PMID 21378987]
Condition Sick sinus syndrome
Gene MYH6
Risk Allele T
pValue 1.5E-29
OR 12.53
95% CI (8.08-19.44)