Total submissions: 2
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Eurofins Ntd Llc |
RCV000307179 | SCV000333859 | uncertain significance | not provided | 2015-08-06 | criteria provided, single submitter | clinical testing | |
Molecular Genetics, |
RCV002225101 | SCV002503658 | uncertain significance | Autosomal recessive limb-girdle muscular dystrophy type 2J | 2022-04-22 | criteria provided, single submitter | clinical testing | This sequence change is predicted to replace glycine with serine at codon 31,812 of the TTN protein, p.(Gly31812Ser), also known as p.(Gly22747Ser). The glycine residue is highly conserved (100 vertebrates, UCSC), and there is a small physicochemical difference between glycine and serine. The variant is present in a large population cohort at a frequency of 0.002%, which is consistent with a recessive disorder (rs754416007, 4/248,396 alleles, 0 homozygotes in gnomAD v2.1.1). The variant has been identified with two other reportable TTN VUS and a VUS in the PLEC gene, in an individual assumed to have a diagnosis of limb-girdle muscular dystrophy or a similar disorder (personal communication, EGL Genetics). A second likely pathogenic TTN variant (p.Glu24230*) has been identified with this variant in a patient with a diagnosis of limb-girdle muscular dystrophy (Royal Melbourne Hospital). This variant is located in the fibronectin type-III (FN3) domain 120 in the A-band of the protein. This domain is adjacent to a myofibrillar myopathy hot spot located in FN3 119, where the disease-causing missense variants are associated with protein mis-folding (PMID: 24636144). Multiple lines of computational evidence have conflicting predictions for the missense substitution (3/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.1.1, this variant is classified as a VARIANT of UNCERTAIN SIGNIFICANCE . Following criteria are met: PM2, PM3_Supporting. |