Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000825529 | SCV000966844 | likely pathogenic | Polyglucosan body myopathy type 2 | 2018-05-30 | criteria provided, single submitter | clinical testing | The c.7+1G>A variant in GYG1 has not been previously reported in individuals wit h Polyglucosan body myopathy, but has been identified in 1/25088 Latino chromoso mes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org ; dbSNP rs949456055). Although this variant has been seen in the general populat ion, its frequency is low enough to be consistent with a recessive carrier frequ ency. This variant occurs in the invariant region (+1) of the splice consensus s equence and is predicted to cause altered splicing leading to an abnormal or abs ent protein. Another variant at this splice junction, c.7G>C, was found as compo und heterozygous with a second GYG1 variant in an individual with Polyglucosan b ody myopathy, and for which RNA analysis demonstrated loss of expression. Loss o f function of the GYG1 gene is an established disease mechanism in autosomal rec essive Polyglucosan body myopathy. In summary, although additional studies are r equired to fully establish its clinical significance, this variant is likely pat hogenic. ACMG/AMP Criteria applied: PVS1_Strong; PM2. |
| Labcorp Genetics |
RCV002536056 | SCV003513097 | likely pathogenic | Glycogen storage disease XV; Polyglucosan body myopathy type 2 | 2023-12-09 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 1 of the GYG1 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in GYG1 are known to be pathogenic (PMID: 20357282, 25272951). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with GYG1-related conditions. ClinVar contains an entry for this variant (Variation ID: 666973). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. |