chr19-38502946-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PP2PP3_Moderate
The NM_000540.3(RYR1):c.7902C>A(p.Asn2634Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,610,608 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. N2634N) has been classified as Likely benign.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.7902C>A | p.Asn2634Lys | missense_variant | 49/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.7902C>A | p.Asn2634Lys | missense_variant | 49/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.7902C>A | p.Asn2634Lys | missense_variant | 49/105 | 1 | P4 | ||
RYR1 | ENST00000594335.5 | c.1356C>A | p.Asn452Lys | missense_variant, NMD_transcript_variant | 10/49 | 1 | |||
RYR1 | ENST00000599547.6 | c.7902C>A | p.Asn2634Lys | missense_variant, NMD_transcript_variant | 49/80 | 2 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152118Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000141 AC: 35AN: 248868Hom.: 0 AF XY: 0.000156 AC XY: 21AN XY: 134778
GnomAD4 exome AF: 0.000112 AC: 163AN: 1458490Hom.: 0 Cov.: 37 AF XY: 0.000127 AC XY: 92AN XY: 725732
GnomAD4 genome AF: 0.000138 AC: 21AN: 152118Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74304
ClinVar
Submissions by phenotype
not provided Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 04, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RYR1 p.Asn2634Lys variant was not identified in the Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs148041292) Clinvitae, LOVD 3.0 and ClinVar (reported as a VUS by the Clinical Molecular Genetics Laboratory at John's Hopkins All Children's Hospital and by the ClinSeq Biesecker Lab at NIH for susceptibility to malignant hyperthermia). The variant was identified in control databases in 38 of 280230 chromosomes at a frequency of 0.000136 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 30 of 129078 chromosomes (freq: 0.000232), Latino in 7 of 35436 chromosomes (freq: 0.000198) and other in 1 of 7206 chromosomes (freq: 0.000139); it was not observed in the African, Ashkenazi Jewish, East Asian, European (Finnish), and South Asian populations. The RYR1 p.Asn2634Lys variant was found in an unaffected individual in a study analyzing 870 control participants for variants in genes related to malignant hyperthermia susceptibility (Gonsalves_2014_PMID: 24195946). The p.Asn2634 residue is not highly conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Malignant hyperthermia, susceptibility to, 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Dec 18, 2023 | This missense variant replaces asparagine with lysine at codon 2634 of the RYR1 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study has shown this variant increases sensitivity to RYR1-agonist 4-CmC when expressed in HEK293T cells compared to cells expressing wild-type RYR1 (PMID: 36208971). This variant has been reported in a family affected with malignant hyperthermia susceptibility (PMID: 36208971). This variant has been identified in 38/280230 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | research | Biesecker Lab/Clinical Genomics Section, National Institutes of Health | Jul 01, 2013 | - - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Jun 20, 2017 | - - |
Congenital myopathy with fiber type disproportion;C0751951:Central core myopathy;C1850674:Congenital multicore myopathy with external ophthalmoplegia;C2930980:Malignant hyperthermia, susceptibility to, 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
RYR1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at