ClinVar Miner

Submissions for variant NM_001035.3(RYR2):c.12667_12669del (p.Lys4223del) (rs794728838)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000182901 SCV000235290 uncertain significance not provided 2017-06-16 criteria provided, single submitter clinical testing The c.12667_12669delAAG variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. c.12667_12669delAAG results in the deletion of a moderately conserved Lysine residue at position 4223 and does not cause a shift in reading frame. Other in-frame deletion/duplication mutations in the RYR2 have been reported in association with CPVT. Additionally, c.12667_12669delAAG is located in the channel region hot spot" of the RYR2 gene (Medeiros-Domingo et al., 2009). However, the NHLBI Exome Sequencing Project reports c.12667_12669delAAG was observed at a low frequency in 1/7990 alleles from individuals of European background and 4/3824 alleles from individuals of African American background, including one individual homozygous for c.12667_12669delAAG. Therefore, it is unclear whether this variant is a pathogenic mutation or a rare benign variant."
Integrated Genetics/Laboratory Corporation of America RCV000781826 SCV000920174 likely benign not specified 2018-07-16 criteria provided, single submitter clinical testing Variant summary: RYR2 c.12667_12669delAAG (p.Lys4223del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 7.6e-05 in 276480 control chromosomes (gnomAD). The observed variant frequency is approximately 1.27 fold of the estimated maximal expected allele frequency for a pathogenic variant in RYR2 causing Arrhythmia phenotype (6e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.12667_12669delAAG in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. One ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "uncertian significance." Based on the evidence outlined above, the variant was classified as likely benign.

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