Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004790035 | SCV005399276 | uncertain significance | Malignant hyperthermia, susceptibility to, 1 | 2020-05-26 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as a 3A-VUS. Following criteria are met: 0103 - Both loss- and gain-of-function are known mechanisms of disease for this gene. (PMID: 23919265). (N) 0108 - This gene is known to be associated with both recessive and dominant disease. (OMIM) (N) 0113 - This gene is known to be imprinted (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from histidine to arginine (exon 4). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD: p.(His110Tyr) 0.0004% (1 heterozygote only) in the European non-Finnish population. (N) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. 4/4 in silico tools. Very highly conserved, although Minor change. (P) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Located in Region 1 / Hotspot domain 1 (PMID: 23919265). (P) 0704 - Comparable variant has low previous evidence for pathogenicity. p.(His110Tyr): ClinVar: Conflicting: VUS x1 + Likely Pathogenic x1). Also, reported in compound heterozygous form with another missense variant in a fetus with akinesia, hydrops, decreased fetal movements, clubfeet and arthrogryposis. Maternally inherited, who was asymptomatic for malignant hyperthermia (PMID: 30652412, also described in PMID: 29261186). (P) 0807 - Variant has not previously been reported in a clinical context. Note: it has been submitted once as a VUS in the LOVD3 Leiden Muscular dystrophy database. (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign |