Submissions for variant NM_005105.5(RBM8A):c.-21G>A

gnomAD frequency: 0.01871  dbSNP: rs139428292

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000081257	SCV000224466	pathogenic	not provided	2015-08-31	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000081257	SCV000596733	other	not provided	2020-04-22	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000023418	SCV000712517	pathogenic	Radial aplasia-thrombocytopenia syndrome	2018-06-15	criteria provided, single submitter	clinical testing	The c.-21G>A variant in RBM8A has been reported in 66 individuals with thrombocy topenia with absent radius (TAR) syndrome in the compound heterozygous state. Si xty-four of these individuals had a submicroscopic deletion encompassing the RBM 8A gene on the other allele, while the two remaining cases had different truncat ing variants on the opposite allele (Albers 2012, Bottillo 2013, Manukjan 2017). In vitro studies demonstrated that this variant may lead to reduced gene expres sion (Albers 2012). This variant has also been reported in ClinVar (Variation ID #30464). Although this variant has been identified in 2.8% (3411/122966) of Euro pean chromosomes and 64 homozygotes by gnomAD (http://gnomad.broadinstitute.org) , loss of function variants in RBM8A are very rare in large population studies, suggesting that compound heterozygosity for the c.-21G>A variant and a loss of f unction variant in RBM8A is also rare. Compound heterozygosity for a hypomorph ( this variant) and a loss of function variant in RBM8A is strongly associated wit h TAR syndrome; however, individuals that are homozygous for the c.-21G>A varian t are not expected to have features of TAR syndrome. In summary, this variant is pathogenic for TAR syndrome in an autosomal recessive manner. ACMG/AMP Criteria applied: PS3, PM3_VeryStrong.
Invitae	RCV000023418	SCV000823560	pathogenic, low penetrance	Radial aplasia-thrombocytopenia syndrome	2024-01-29	criteria provided, single submitter	clinical testing	This variant occurs in a non-coding region of the RBM8A gene. It does not change the encoded amino acid sequence of the RBM8A protein. This variant is present in population databases (rs139428292, gnomAD 2.8%), including at least one homozygous and/or hemizygous individual. This variant has been observed in individual(s) with TAR Syndrome (PMID: 22366785, 24220582, 27320760). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30464). Studies have shown that this variant alters RBM8A gene expression (PMID: 22366785). In summary, this variant is reported to cause disease. However, as this variant is associated with a lower penetrance than other pathogenic alleles in the RBM8A gene, it has been classified as Pathogenic (low penetrance).
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000023418	SCV001164572	pathogenic	Radial aplasia-thrombocytopenia syndrome	2018-12-03	criteria provided, single submitter	research	The heterozygous c.-21G>A variant in RBM8A was identified by our study in one individual in the compound heterozygous state, with a copy number variant, with Thrombocytopenia Absent Radius syndrome (TAR). This variant has been identified in 1.812% (4778/2263746) of chromosomes, including 63 homozygous individuals, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139428292). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role in the compound heterozygous state. The c.-21G>A variant in RBM8A has been reported in the heterozygous state, with a deletion or frameshift variant, in 39 individuals with TAR (PMID: 22366785). Trio exome analysis in the literature showed this variant to be de novo in at least 8 individuals (PMID: 22366785). The presence of this variant in combination with a reported pathogenic variant and in an individual with TAR increases the likelihood that the c.-21G>A variant is pathogenic in the compound heterozygous state, though not the homozygous state. This variant has also been reported pathogenic and likely pathogenic in ClinVar (Variation ID: 30464). The c.-21G>A variant is pathogenic based off of our findings, multiple de novo reports in the literature, and ClinVar. ACMG/AMP Criteria applied: PM3_Strong, PM6_Strong (Richards 2015).
UNC Molecular Genetics Laboratory, University of North Carolina at Chapel Hill	RCV000023418	SCV001251535	likely pathogenic	Radial aplasia-thrombocytopenia syndrome		criteria provided, single submitter	research	The RBM8A c.-21G>A (p.?) variant is a pathogenic variant that is located in the 5' noncoding, untranslated region (5' UTR) of the RBM8A gene. This variant is associated with reduced RBM8A gene activity, and is a mild (hypomorphic) variant that is associated with thrombocytopenia absent radius (TAR) syndrome only in the presence of a more severe, loss-of-function RBM8A variant in trans (PMID: 22366785; 24053387).
CeGaT Center for Human Genetics Tuebingen	RCV000081257	SCV001334605	uncertain significance	not provided	2024-01-01	criteria provided, single submitter	clinical testing	RBM8A: PS4:Moderate, PS3:Supporting
Baylor Genetics	RCV000023418	SCV001521604	pathogenic	Radial aplasia-thrombocytopenia syndrome	2020-12-09	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Genome-Nilou Lab	RCV000023418	SCV001623485	likely pathogenic	Radial aplasia-thrombocytopenia syndrome	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000081257	SCV001989050	pathogenic	not provided	2020-04-21	criteria provided, single submitter	clinical testing	Published functional studies suggest a damaging effect due to disruption of transcription factor binding and reduced transcription of RBM8A, indicating that this is a hypomorphic allele (Albers et al., 2012); Nucleotide substitution has no predicted effect on splicing and is not conserved across species; Located in a region that tolerates variation and lacks pathogenic variants; This variant is associated with the following publications: (PMID: 25813282, 24053387, 22366785, 28556904, 32981126, 27320760, 24220582, 30385887, 30609409, 29595812, 20301781, 32227665, 28857120, 28983057, 32333414)
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV000023418	SCV002495917	pathogenic	Radial aplasia-thrombocytopenia syndrome	2022-10-12	criteria provided, single submitter	clinical testing	This variant has been reported in the literature in numerous individuals with thrombocytopenia-absent radius (TAR) syndrome, most often as a compound heterozygote in trans with a recurrent 200kb deletion (Selected publications: Albers 2012 PMID: 22366785; Bottillo 2013 PMID: 24053387; Bastida 2018 PMID: 28983057; Boussion 2020 PMID: 32227665) and is present in the GeneReviews entry for this gene (Toriello 2016 PMID: 20301781). Of note, individuals who carry this variant in the homozygous state have typically not been found in association with disease (Toriello 2016 PMID: 20301781). This variant is present in the Genome Aggregation Database (Highest reported MAF: 2.8% [3411/122966], including in 64 total homozygotes (https://gnomad.broadinstitute.org/variant/1-145507646-G-A?dataset=gnomad_r2_1). This variant is also present in ClinVar, with several labs classifying this variant as Pathogenic (Variation ID: 30464). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. Of note, this variant occurs in the 5' UTR of this gene and does not change the coding sequence; however, literature suggests that this variant affects promoter activity and functions as a hypomorphic allele (Albers 2012 PMID: 22366785). In summary, although this variant occurs at a high minor allele frequency, there is significant evidence suggesting a disease-causing impact of this variant and it is thus classified as pathogenic, but may be best regarded as a a hypomorphic allele.
Mendelics	RCV000023418	SCV002518969	pathogenic	Radial aplasia-thrombocytopenia syndrome	2022-05-04	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000023418	SCV002572396	pathogenic	Radial aplasia-thrombocytopenia syndrome	2022-08-03	criteria provided, single submitter	clinical testing	Variant summary: RBM8A c.-21G>A is located in the untranslated mRNA region upstream of the initiation codon. 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 0.018 in 237842 control chromosomes in the gnomAD database, including 61 homozygotes. c.-21G>A has been reported in the literature in multiple individuals affected with Radial Aplasia-Thrombocytopenia Syndrome. These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed that variant resulted in decreased promoter activity (Albers_2012). Twelve clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000023418	SCV002809850	pathogenic	Radial aplasia-thrombocytopenia syndrome	2022-04-13	criteria provided, single submitter	clinical testing
Daryl Scott Lab, Baylor College of Medicine	RCV000023418	SCV003915708	pathogenic	Radial aplasia-thrombocytopenia syndrome	2023-04-11	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University Hospital of Duesseldorf	RCV000023418	SCV004046691	likely pathogenic	Radial aplasia-thrombocytopenia syndrome		criteria provided, single submitter	not provided
PreventionGenetics, part of Exact Sciences	RCV003390698	SCV004121558	pathogenic	RBM8A-related condition	2023-09-13	criteria provided, single submitter	clinical testing	The RBM8A c.-21G>A variant is located in the 5' untranslated region. The c.-21G>A substitution is found in apparently unaffected individuals at frequencies over 2.7% (Albers et al. 2012. PubMed ID: 22366785; see also gnomAD database). However, significant evidence suggests the c.-21G>A substitution is a “functional polymorphism” and that when paired with a null RBM8A allele, such as a large 1q21.1 deletion identified in most TAR patients, is likely a cause of thrombocytopenia with absent radius (TAR) (Albers et al. 2012. PubMed ID: 22366785; Bottillo et al. 2013. PubMed ID: 24053387). Using a cell-based, biochemical assay, studies from Albers et al. 2012 show that the c.-21G>A substitution may decrease transcription of a reporter gene and therefore, when found in patients also harboring a null RBM8A allele, may result in reduction of RBM8A protein to levels below a critical threshold required by some cell types. In summary, the c.-21G>A variant has been found in a high proportion of patients with TAR who also have a large deletion on the opposite allele that includes the RBM8A gene. However, individuals that are homozygous for the c.-21 G>A variant are not expected to have features of TAR syndrome (Bottillo et al. 2013. PubMed ID: 24053387; see also gnomAD database). Based on the collective evidence, we interpret this variant as pathogenic.
Mayo Clinic Laboratories, Mayo Clinic	RCV000081257	SCV004226716	pathogenic	not provided	2022-07-06	criteria provided, single submitter	clinical testing	PP4, PM3, PS3
Clinical Genomics Program, Stanford Medicine	RCV000023418	SCV004232357	pathogenic	Radial aplasia-thrombocytopenia syndrome	2021-04-05	criteria provided, single submitter	clinical testing	The c.-21G>A variant in the RBM8A gene is a reported cause of thrombocytopenia absent radius syndrome (Albers et al., 2012; Boussion et al., 2020). This variant in the homozygous state does not cause thrombocytopenia absent radius syndrome; however, this variant in conjunction with a loss of function variant is a common cause of thrombocytopenia absent radius syndrome. The c.-21G>A variant was determined to be in trans with a pathogenic variant (1q21.1 deletion) consistent with autosomal recessive inheritance (Albers et al., 2012; Boussion et al., 2020). The presence of this variant with an established disease-causing variant on the opposite allele increases suspicion for its pathogenicity. This variant has been identified in 3,411/122,966 European chromosomes by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is consistent with a recessive carrier frequency for a mild allele. Well-established in vitro functional studies of the c.-21G>A variant strongly suggest it reduces protein expression that is sufficient to be disease-causing (Albers et al., 2012; Boussion et al., 2020). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the c.-21G>A variant as pathogenic for autosomal recessive thrombocytopenia absent radius (TAR) syndrome based on the information above. [ACMG evidence codes used: PS3; PM3_verystrong]
Johns Hopkins Genomics, Johns Hopkins University	RCV000023418	SCV004239095	pathogenic	Radial aplasia-thrombocytopenia syndrome	2023-08-01	criteria provided, single submitter	clinical testing
OMIM	RCV000023418	SCV000044709	pathogenic	Radial aplasia-thrombocytopenia syndrome	2012-02-26	no assertion criteria provided	literature only
GeneReviews	RCV000023418	SCV000086918	not provided	Radial aplasia-thrombocytopenia syndrome		no assertion provided	literature only
Genomic Research Center, Shahid Beheshti University of Medical Sciences	RCV000023418	SCV000121618	pathogenic	Radial aplasia-thrombocytopenia syndrome	2022-12-24	no assertion criteria provided	not provided	Converted during submission to Pathogenic.
Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	RCV000023418	SCV001469139	pathogenic	Radial aplasia-thrombocytopenia syndrome	2020-08-07	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000081257	SCV001744790	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000081257	SCV001957788	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000081257	SCV001972588	pathogenic	not provided		no assertion criteria provided	clinical testing
ISTH-SSC Genomics in Thrombosis and Hemostasis, KU Leuven, Center for Molecular and Vascular Biology	RCV000023418	SCV002515678	pathogenic	Radial aplasia-thrombocytopenia syndrome		no assertion criteria provided	research
Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	RCV000023418	SCV004099310	likely pathogenic	Radial aplasia-thrombocytopenia syndrome	2023-10-30	no assertion criteria provided	clinical testing