ClinVar Genomic variation as it relates to human health

This variant is associated with the following publications: (PMID: 25163546)

Variant summary: RBM20 c.1880+4_1880+6dupAGG alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 156316 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is approximately 22 fold of the estimated maximal expected allele frequency for a pathogenic variant in RBM20 causing Dilated Cardiomyopathy phenotype (4.7e-05), strongly suggesting that the variant is benign. c.1880+4_1880+6dupAGG has been reported in the literature in sequencing studies reporting individuals affected with sporadic or familial Dialated Cardiomyopathy (example, Haas_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Dilated Cardiomyopathy. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (VUS, n=1; likely benign, n=3, benign, n=1). One submitter reports this variant as having co-occurred with another pathogenic variant that clearly explained the patient phenotype. Based on the evidence outlined above, the variant was classified as benign.

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

RBM20: BP4, BS1, BS2

The c.1880+4_1880+6dupAGG variant in RBM20 is classified as likely benign because it has been identified in 0.2% (177/75818) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1.

RBM20 NM_001134363.2 exon 8 c.1880+4_1880+6dup: This variant has been reported in the literature in at least one individual with DCM (Haas 2015 PMID:25163546). However, this variant is also present in 0.2% (177/75818) of European alleles in the Genome Aggregation Database, including 2 homozygotes (https://gnomad.broadinstitute.org/variant/10-112570222-T-TGAG) and is present in ClinVar, with several labs classifying this variant as likely benign (Variation ID:43978). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Although this variant occurs in the splice region, computational prediction tools do not suggest that it alters splicing. However, further studies are needed to understand its impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.