Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000333472 | SCV000345086 | uncertain significance | not provided | 2016-09-23 | criteria provided, single submitter | clinical testing | |
Invitae | RCV000812750 | SCV000953073 | likely pathogenic | Qualitative or quantitative defects of dysferlin | 2021-10-05 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine with histidine at codon 221 of the DYSF protein (p.Gln221His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 290515). This missense change has been observed in individual(s) with dysferlinopathy (Invitae). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). |