ClinVar

Description

Based on the classification scheme VCGS_Germline_v1.3.3, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with glomuvenous malformations (MIM#138000). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance. In a cohort of 162 families, penetrance was estimated to be approximately 90% (PMID:23801931). (I) 0115 - Variants in this gene are known to have variable expressivity. Significant phenotypic variability is reported even among affected family members, and may be influenced by somatically-acquired 'second hits' (PMID:23801931, 23375657). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Variants predicted to cause NMD are the most common variant type reported in affected individuals (ClinVar, PMID:23801931). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported in at least nine unrelated individuals with glomuvenous malformations (ClinVar, PMID:23801931, 15689436). (SP) 1007 - No published functional 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