Submissions for variant NM_001134363.3(RBM20):c.676G>A (p.Ala226Thr)

gnomAD frequency: 0.00001  dbSNP: rs1033220280

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001359380	SCV001555247	uncertain significance	Dilated cardiomyopathy 1DD	2022-01-01	criteria provided, single submitter	clinical testing	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RBM20 protein function. ClinVar contains an entry for this variant (Variation ID: 1051356). This variant has not been reported in the literature in individuals affected with RBM20-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.001%). This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 226 of the RBM20 protein (p.Ala226Thr).
Fulgent Genetics, Fulgent Genetics	RCV001359380	SCV002816067	uncertain significance	Dilated cardiomyopathy 1DD	2021-08-21	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001359380	SCV003920384	uncertain significance	Dilated cardiomyopathy 1DD	2021-03-30	criteria provided, single submitter	clinical testing	RBM20 NM_001134363.2 exon 2 p.Ala226Thr (c.676G>A): This variant has not been reported in the literature but is present in 1/15004 European alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant amino acid Threonine (Thr) is present in several species and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003399158	SCV004121858	uncertain significance	not specified	2023-10-19	criteria provided, single submitter	clinical testing
GeneDx	RCV004590349	SCV005080373	uncertain significance	not provided	2024-06-12	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis indicates that this missense variant does not alter protein structure/function
Ambry Genetics	RCV004988590	SCV005493339	likely benign	Cardiovascular phenotype	2024-07-24	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.