Submissions for variant NM_001029.5(RPS26):c.3+1G>T

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV002435658	SCV002750774	likely pathogenic	Diamond-Blackfan anemia	2018-08-08	criteria provided, single submitter	clinical testing	The c.3+1G>T intronic variant results from a G to T substitution one nucleotide after coding exon 1 of the RPS26 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Two alterations at the same nucleotide position, c.3+1G>C and c.3+1G>A, have been described in unrelated probands with Diamond Blackfan anemia (DBA) (Doherty L et al. Am. J. Hum. Genet., 2010 Feb;86:222-8). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV003225993	SCV003922305	pathogenic	Diamond-Blackfan anemia 10	2023-05-02	criteria provided, single submitter	curation	The heterozygous c.3+1G>T variant in RPS26 was identified by our study in one individual with anemia with erythroid hyperplasia, genitourinary anomalies, short stature, cleft upper lip, and cleft palate. Trio exome analysis showed this variant to be de novo. The c.3+1G>T variant in RPS26 has been previously reported in one individual with Diamond-Blackfan anemia 10 (PMID: 31401766). This variant was absent from large population studies. Two different nucleotide changes that also result in a splice donor variant at the same site, c.3+1G>A (PMID: 20116044, ClinVar Variation ID: 6126) and c.3+1G>C (PMID: 24675553), have been previously reported likely pathogenic, and the variant being assessed here, c.3+1G>T, is predicted by SpliceAI to have a similar effect on splicing. This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Heterozygous loss of function of the RPS26 gene is an established disease mechanism in Diamond-Blackfan anemia 10. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant Diamond-Blackfan anemia 10. ACMG/AMP Criteria applied: PVS1, PS1_Supporting, PS2, PS4_Supporting, PM2_Supporting (Richards 2015).