ClinVar Genomic variation as it relates to human health

The SNRPB c.155+301G>C variant is predicted to interfere with splicing. This variant has frequently been reported to occur de novo in patients with Cerebro-costo-mandibular syndrome (CCMS) (Lynch et al 2014. PubMed ID: 25047197; Patient 2, Supplemental Table S1, Bacrot et al 2014. PubMed ID: 25504470; Table 2, Tooley et al 2016. PubMed ID: 26971886). This variant results in the inclusion of a regulatory exon that triggers nonsense-mediated mRNA decay of the transcript (Lynch et al 2014. PubMed ID: 25047197). Prenatal presentations of CCMS can include increased nuchal translucency, intrauterine growth retardation, polyhydraminos, and micrognathia (Tooley et al 2016. PubMed ID: 26971886). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic.

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0104 - Dominant negative is a known mechanism of disease in this gene and is associated with cerebrocostomandibular syndrome (MIM#117650). Pathogenic variants cluster at two conserved exonic splicing silencer regulatory sites in a premature termination codon (PTC) containing alternative exon, which undergoes nonsense-mediated decay and serves to regulate expression of the functional transcripts. Pathogenic variants promote the inclusion of the PTC-containing alternative exon, resulting in reduced expression of the functional transcripts (PMID: 25047197, 25504470, 26971886). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0217 - Non-coding variant with known effect. This intronic variant also results in a missense variant in a regulatory exon of the alternative PTC-containing transcript (ENST00000474384:c.165G>C; p.(Arg55Ser)). This alternative transcript is important for regulation of SNRPB expression, a gene that encodes core components of major spliceosome subunits. The variant results in increased expression of the PTC-containing transcript, inclusion of an alternative exon, and an overall decrease in total SNRPB expression (PMID: 25047197). (SP) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0311 - Alternative nucleotide changes at the same intronic position have been observed in gnomAD (v2 & v3) (highest allele count: 16 heterozygotes, 0 homozygotes). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. The variant has previously been reported as pathogenic in multiple individuals with cerebrocostomandibular syndrome (MIM#117650), many of whom were de novo, and is often annotated as g.2447952C>G (GRCh37) using the genomic location (ClinVar, LOVD, PMID: 25047197, PMID: 26971886). (SP) 1101 - Very strong and specific phenotype match for this individual. (SP) 1203 - This variant has been shown to be de novo in the proband (parental status confirmed; by trio analysis). (SP) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this variant does not alter splicing; This variant is associated with the following publications: (PMID: 25504470, 25047197, 26971886, 26240113, 35982159, 37161864, 33057194)

The c.155+301G>C variant in the SNRPB gene has been previously reported in 10 unrelated individuals with cerebro-costo-mandibular syndrome(identified de novo in 6 of those individuals)and co-segregated with disease in 1 affected relative (Bacrot et al., 2015; Lynch et al., 2014; Tooley et al., 2016). This variant was absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/).Functional studies ofthe c.155+301G>C variant demonstrated an increased level of regulatory transcript and decreased levels of functional transcript in patient cells(Bacrot et al., 2015; Lynch et al., 2014).This variant is located in the alternate exon in the regulatory PTC transcript of SNRPB. Other pathogenic and likely pathogenic variants have been described in this exon and lead to increased transcription of the regulatory PTC transcript and decreased transcription of the functional protein coding transcripts. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.155+301G>C variant as pathogenic for autosomal dominant cerebro-costo-mandibular syndrome based on the information above.[ACMG evidence codes used: PS3_Supporting; PM1; PM2; PM6_VeryStrong]