Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV004788420 | SCV005400305 | likely pathogenic | Dilated cardiomyopathy 1G | 2024-09-20 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene. In addition, dominant-negative is also a suggested mechanism. (PMID: 25589632). (I) 0108 - This gene is associated with both recessive and dominant disease (OMIM). (I) 0112 - The condition associated with this gene has incomplete penetrance. Variants in this gene that result in a premature truncating codon (PTC) are known to have reduced penetrance in DCM (PMID: 25589632). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. This missense variant has been proven to create a novel donor gain splicing event, causing a deletion of the last 40 nucleotides of the exon, resulting in a frameshift and premature termination codon five amino acids downstream, p.(Ala1536Leufs*6). This variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (personal communication with The Victor Chang Cardiac Research Institute, PMID: 28424332). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - Multiple alternative amino acid changes at the same position have been observed in gnomAD (v2) (highest allele count: 1 heterozygote, 0 homozygote). (I) 0600 - Variant is located near the annotated Z-disk and the exon has a PSI score of 100% (PMID: 25589632). (I) 0702 - Other NMD-predicted variants comparable to the one identified in this case have strong previous evidence for pathogenicity (ClinVar). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant was inherited in trans with another variant in an individual with multi/minicore congenital myopathy (LOVD, PMID: 28424332). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |