Submissions for variant NM_005105.5(RBM8A):c.*6C>G

gnomAD frequency: 0.04454  dbSNP: rs12079762

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000081256	SCV001900929	likely pathogenic	not provided	2024-03-26	criteria provided, single submitter	clinical testing	Hypomorphic allele that is only associated with disease when in trans with a null RBM8A allele, most frequently the 1q21.1 deletion (PMID: 32227665); Published functional studies suggest reduced expression consistent with a hypomorphic allele (PMID: 32227665); Nucleotide is not conserved across species and the substitution has no predicted effect on splicing; This variant is associated with the following publications: (PMID: 32552793, 33559987, 33718801, Poulos2023[posterabstract], 32227665)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002055193	SCV002495918	likely pathogenic	Radial aplasia-thrombocytopenia syndrome	2022-03-28	criteria provided, single submitter	clinical testing	RBM8A NM_005105.4 exon 6 (3'-UTR) c.*6C>G: This variant has been reported in the literature in the compound heterozygous state in at least 14 individuals with Thrombocytopenia with Absent Radii (TAR) syndrome, most often in trans with a recurrent 200 kb deletion (Selected publications: Boussion 2020 PMID:32227665; Gálvez 2020 PMID:33718801; Morgan 2021 PMID:33559987). This variant is present in 14.2% (5886/41376) of African/African American alleles, including 454 homozygotes, in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-145925876-G-C?dataset=gnomad_r3). This variant is present in ClinVar, with classifications ranging from Variant of Uncertain Significance to Likely Pathogenic (Variation ID:95245). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant occurs in the 3'-UTR of this gene and does not change the coding sequence; however, literature suggests that this variant affects transcript regulation and functions as a hypomorphic allele (Albers 2012 PMID:22366785; Boussion 2020 PMID:32227665). In summary, although this variant occurs at a high minor allele frequency, there is significant evidence supporting a disease-causing impact of this variant when in trans with a null allele (Boussion 2020 PMID:32227665). Therefore, it is classified as Likely Pathogenic, but may be best regarded as a hypomorphic allele.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002055193	SCV004021004	likely pathogenic	Radial aplasia-thrombocytopenia syndrome	2023-06-27	criteria provided, single submitter	clinical testing	Variant summary: RBM8A c.*6C>G is located in the untranslated mRNA region downstream of the termination codon. The variant allele was found at a frequency of 0.014 in 249874 control chromosomes, predominantly at a frequency of 0.15 within the African or African-American subpopulation in the gnomAD database, including 195 homozygotes. The observed variant frequency and the high number of homozygotes suggests that the variant is benign when found in homozygous state. On the other hand, c.*6C>G has been reported in the literature in several compound heterozygous individuals, always in trans with a null allele (particularly a 1q21.1 deletion), who were affected with Radial Aplasia-Thrombocytopenia Syndrome, and the variant has been shown to segregate with disease in related individuals from multiple different families (e.g, Boussion_2020, deRocha_2021, Galvez_2021, Morgan_2020). These data suggest that the pathogenicity of the variant is genotype-dependent, i.e. highly dependent on the variant observed in trans. A publication reported experimental evidence evaluating the effect of the variant, and demonstrated that the variant resulted in reduced expression (corresponding to ~70 of the WT levels), consistent with a hypomorphic allele (Boussion_2020). The following publications have been ascertained in the context of this evaluation (PMID: 32227665, 33718801, 33559987, 34341987). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments: two submitters classified the variant as likely pathogenic, and one submitter classified it as VUS. Based on the evidence outlined above, the variant represents a hypomorphic allele that is subject to interallelic interactions, however it causes disease when in trans with a null allele, therefore, the variant was classified as likely pathogenic.
PreventionGenetics, part of Exact Sciences	RCV003398675	SCV004119244	likely pathogenic	RBM8A-related disorder	2024-01-05	criteria provided, single submitter	clinical testing	The RBM8A c.*6C>G variant is located in the 3' untranslated region. While the c.*6C>G variant is found at a high frequency (up to ~15% in gnomAD); it appears to also be found regularly in patients with thrombocytopenia with absent radius (TAR) who harbor a 1q21.1 deletion, and functional data suggest it is a hypomorphic allele, similar to the well-established hypomorphic alleles c.-21G>A and c.67+32G>C found frequently in TAR patients (Boussion et al. 2020. PubMed ID: 32227665). We characterize this variant as likely pathogenic. Of note, we did not detect a 1q21.1 deletion or another loss of function variant in the RBM8A gene in this patient. The c.*6C>G variant in the homozygous state, in the absence of another pathogenic variant in the RBM8A gene, is less likely to contribute to disease.
CeGaT Center for Human Genetics Tuebingen	RCV000081256	SCV004699352	benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	RBM8A: BS1, BS2
Illumina Laboratory Services, Illumina	RCV002055193	SCV004801412	likely pathogenic	Radial aplasia-thrombocytopenia syndrome	2021-04-28	criteria provided, single submitter	clinical testing	The RBM8A c.6*C>G variant is a 3'UTR variant that has been reported in at least 12 individuals with TAR syndrome in trans with a pathogenic 1q21.1 or 1q21.1q21.2 deletion with at least five originating from different families (Boussion et al. 2020; Morgan et al. 2020; da Rocha et al. 2021; Galvez et al. 2021). The c.6*C>G variant, segregated with the disorder in multiple affected individuals in at least three families (Boussion et al. 2020). In vitro luciferase reporter assay shows reduced expression of the RBM8A c.6*C>G construct as compared to the wild-type protein (Boussion et al. 2020). The c.6*C>G variant is found at a frequency of 0.1483 in the African/African American subpopulation of the Genome Aggregation Database (version 2.1.1). Even though this frequency is high, it does not preclude this variant's potentially damaging effect, as hypomorphic variants along with a heterozygous loss of function are a typical mechanism of TAR syndrome (Boussion et al. 2020). Based on the collective evidence, the c.6*C>G variant is classified as a likely pathogenic hypomorphic variant for TAR syndrome.
Baylor Genetics	RCV002055193	SCV005049731	likely pathogenic	Radial aplasia-thrombocytopenia syndrome	2024-03-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000081256	SCV005413707	likely pathogenic	not provided	2023-12-26	criteria provided, single submitter	clinical testing	BA1, PM3, PS3, PS4_supporting
Eurofins Ntd Llc (ga)	RCV000081256	SCV000113164	uncertain significance	not provided	2017-04-17	flagged submission	clinical testing