rs750938678
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6
The NM_000540.3(RYR1):c.2603G>A(p.Arg868His) variant causes a missense change. The variant allele was found at a frequency of 0.000258 in 1,613,936 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R868C) has been classified as Uncertain significance.
Frequency
Consequence
NM_000540.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RYR1 | NM_000540.3 | c.2603G>A | p.Arg868His | missense_variant | 21/106 | ENST00000359596.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RYR1 | ENST00000359596.8 | c.2603G>A | p.Arg868His | missense_variant | 21/106 | 5 | NM_000540.3 | A2 | |
RYR1 | ENST00000355481.8 | c.2603G>A | p.Arg868His | missense_variant | 21/105 | 1 | P4 | ||
RYR1 | ENST00000599547.6 | c.2603G>A | p.Arg868His | missense_variant, NMD_transcript_variant | 21/80 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.000171 AC: 26AN: 152164Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000662 AC: 166AN: 250922Hom.: 0 AF XY: 0.000553 AC XY: 75AN XY: 135706
GnomAD4 exome AF: 0.000268 AC: 391AN: 1461654Hom.: 1 Cov.: 33 AF XY: 0.000305 AC XY: 222AN XY: 727146
GnomAD4 genome ? AF: 0.000171 AC: 26AN: 152282Hom.: 0 Cov.: 31 AF XY: 0.000242 AC XY: 18AN XY: 74464
ClinVar
Submissions by phenotype
not specified Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Mar 27, 2017 | The R868H variant has been previously reported in an individual with central core disease, however, this variant was noted to be inherited from an asymptomatic parent (Snoeck et al., 2015). The R868H variant is observed in 43/16330 (0.26%) alleles from individuals of South Asian background in large population cohorts, and 1 homozygous individual undergoing testing at GeneDx (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). This variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved in mammals, and in silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Uncertain significance, criteria provided, single submitter | curation | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Jan 22, 2020 | The p.Arg868His variant in RYR1 has been reported in one individual with Central Core Disease, the individual's asymptomatic parent, and 1 homozygous individual undergoing genetic testing through GeneDx (PMID: 25960145; Variation ID: 419631), and has been identified in 0.2614% (80/30610) of South Asian chromosomes, 0.2258% (80/35428) of Latino chromosomes, and 0.002327% (3/128944) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs750938678). This variant has also been reported as a VUS and likely benign variant in ClinVar (Variation ID: 419631). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional variant, resulting in a different amino acid change at the same position, p.Arg868Cys, has been reported as a VUS in association with disease in ClinVar (Variation ID: 590504). In summary, while the clinical significance of the p.Arg868His variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1 (Richards 2015). - |
Congenital multicore myopathy with external ophthalmoplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 02, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
RYR1-related condition Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Oct 02, 2023 | The RYR1 c.2603G>A variant is predicted to result in the amino acid substitution p.Arg868His. This variant has been previously reported as a variant of uncertain significance in single patient with central core disease, but the variant was also found heterozygous in the asymptomatic parent (Snoeck et al. 2015. PubMed ID: 25960145). The c.2603G>A variant has an allele frequency of 0.26% in individuals of South Asian descent in gnomAD (https://gnomad.broadinstitute.org/variant/chr19-38954088-G-A) and has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/419631/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Malignant hyperthermia, susceptibility to, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Aug 02, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | May 24, 2023 | - - |
RYR1-Related Disorders Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 30, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at