ClinVar Miner

Submissions for variant NM_000540.3(RYR1):c.10274C>T (p.Thr3425Met)

gnomAD frequency: 0.00006  dbSNP: rs150977342
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000699049 SCV000827744 likely benign RYR1-related disorder 2024-11-04 criteria provided, single submitter clinical testing
Baylor Genetics RCV001331318 SCV001523335 uncertain significance Central core myopathy 2019-03-01 criteria provided, single submitter clinical testing This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Revvity Omics, Revvity RCV003130009 SCV003813116 uncertain significance not provided 2021-04-01 criteria provided, single submitter clinical testing
CeGaT Center for Human Genetics Tuebingen RCV003130009 SCV004811308 uncertain significance not provided 2024-03-01 criteria provided, single submitter clinical testing
Ambry Genetics RCV004026463 SCV004945793 uncertain significance Inborn genetic diseases 2023-09-20 criteria provided, single submitter clinical testing The c.10274C>T (p.T3425M) alteration is located in exon 68 (coding exon 68) of the RYR1 gene. This alteration results from a C to T substitution at nucleotide position 10274, causing the threonine (T) at amino acid position 3425 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004788135 SCV005399342 uncertain significance RYR1-related myopathy 2020-05-21 criteria provided, single submitter clinical testing A heterozygous missense variant was identified, NM_000540.2(RYR1):c.10274C>T in exon 68 of 106 of the RYR1 gene. This substitution is predicted to create a moderate amino acid change from a threonine to a methionine at position 3425 of the protein; NP_000531.2(RYR1):p.(Thr3425Met). The threonine at this position has low conservation (100 vertebrates, UCSC), and is not situated in a known functional domain. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD database at a global population frequency of 0.012% (27 heterozygotes, 0 homozygotes) with a South Asian sub-population frequency of 0.048%. Two alternative residue changes at the same location have been reported in the gnomAD database at a frequency of 0.015% and 0.0026%. This variant has been previously reported as a VUS in patient with RYR1-related disorder (ClinVar). Based on information available at the time of curation, this variant has been classified as a VUS.
GeneDx RCV003130009 SCV005439377 uncertain significance not provided 2024-06-21 criteria provided, single submitter clinical testing In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge

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