Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Victorian Clinical Genetics Services, |
RCV002471815 | SCV002766783 | likely pathogenic | Cardiac anomalies - developmental delay - facial dysmorphism syndrome | 2023-07-17 | 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 and is associated with impaired intellectual development and distinctive facial features with or without cardiac defects (MIM#616789). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity, in terms of the presence of cardiac defects (PMID: 29511999). (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Minigene analysis showed activation of a cryptic acceptor splice site at 8bp downstream, expected to result in a frameshift p.(Arg671Serfs*4) predicted to cause nonsense-mediated decay (NMD) (Prof. Robert J. Harvey, University of the Sunshine Coast). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2, v3: 16 heterozygotes, 0 homozygotes); however, it has been flagged as potentially a low quality site. (I) 0505 - Abnormal splicing is predicted by in silico tools and affected nucleotide is highly conserved. (SP) 0701 - Other premature termination variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants in this gene have been reported as likely pathogenic/pathogenic (ClinVar). Another variant at this canonical splice site (c.2013-2A>T) has inconclusive previous evidence for pathogenicity. It has been reported as benign by a clinical testing laboratory but without further information provided (ClinVar). It has also been reported in a family with lateral temporal epilepsy with a causal variant in the RELN gene. The MED13L c.2013-2A>T variant was detected via whole exome sequencing and was listed as potentially deleterious (PMID: 26046367). (SP) 0806 - This variant has low previous evidence of being benign in unrelated individuals. This variant has been reported once as likely benign in LOVD. However, no evidence was provided and therefore was not taken into consideration during our classification. (I) 0906 - Segregation evidence for this variant is inconclusive. This variant is heterozygous in the affected sister, and absent in an unaffected sister. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1207 - Parental origin of the variant is unresolved. This variant is not maternally inherited; however, a sample from this individual's father has not been tested. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |