Submissions for variant NM_001134363.3(RBM20):c.2116C>A (p.Pro706Thr)

gnomAD frequency: 0.00007  dbSNP: rs373797219

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000766692	SCV000236311	uncertain significance	not provided	2023-12-26	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000183829	SCV000270786	likely benign	not specified	2015-05-01	criteria provided, single submitter	clinical testing	p.Pro706Thr in exon 9 of RBM20: This variant is not expected to have clinical si gnificance due to a lack of conservation across species, including mammals. Of n ote, >20 mammals have a threonine (Thr) at this position despite high nearby ami no acid conservation. In addition, computational prediction tools do not suggest a high likelihood of impact to the protein. It has also been identified in 1/31 82 European American chromosomes by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS/; dbSNP rs373797219).
Labcorp Genetics (formerly Invitae), Labcorp	RCV000685352	SCV000812830	likely benign	Dilated cardiomyopathy 1DD	2025-01-14	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV000769269	SCV000900645	uncertain significance	Cardiomyopathy	2017-10-30	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000685352	SCV002557058	uncertain significance	Dilated cardiomyopathy 1DD	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3C. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with dilated cardiomyopathy, 1DD (MIM#613172) (OMIM). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to threonine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (13 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0503 - Missense variant consistently predicted to be tolerated by multiple in silico tools or not conserved in placental mammals with a minor amino acid change. (SB) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported in a family with DCM, although this variant was shown not to segregate with disease in this family (PMID: 29892087). This variant has also been reported as a VUS and likely benign in ClinVar and Global Variome shared LOVD. (I) 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
Ambry Genetics	RCV002415789	SCV002726409	likely benign	Cardiovascular phenotype	2023-05-25	criteria provided, single submitter	clinical testing	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.
Clinical Genomics Laboratory, Stanford Medicine	RCV000685352	SCV004805227	uncertain significance	Dilated cardiomyopathy 1DD	2021-06-07	criteria provided, single submitter	clinical testing	The p.Pro706Thr variant in the RBM20 gene has not been previously reported in association with disease. This variant has been identified in 13/186,024 chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, it has not been observed at a frequency high enough to rule out pathogenicity. The proline at position 706 is not evolutionarily conserved and several mammalian species have a threonine at this position. Computational tools predict that the p.Pro706Thr does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Pro706Thr variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP4]
Mayo Clinic Laboratories, Mayo Clinic	RCV000766692	SCV005412232	uncertain significance	not provided	2024-08-22	criteria provided, single submitter	clinical testing	BP4