Submissions for variant NM_000975.5(RPL11):c.60_61del (p.Cys21fs)

dbSNP: rs1570566590

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000006108	SCV002507058	pathogenic	Diamond-Blackfan anemia 7	2022-05-04	criteria provided, single submitter	curation	The heterozygous p.Cys21SerfsTer33 variant in RPL11 was identified by our study in one individual with Diamond-Blackfan anemia 7 (DBA7). Trio exome analysis showed this variant to be de novo. The variant has been reported in 5 individuals of Italian and unknown ethnicity with DBA7 (PMID: 19773262, 19061985), but was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 21 and leads to a premature termination codon 33 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Heterozygous loss of function of the RPL11 gene is a moderately established disease mechanism in DBA7. In summary, this variant meets criteria to be classified as pathogenic for DBA7 in an autosomal dominant manner based on the predicted loss of function impact of the variant and its de novo occurrence. ACMG/AMP Criteria applied: PS2, PVS1_strong, PM2, PS4_supporting (Richards 2015).
Ambry Genetics	RCV002354149	SCV002656170	pathogenic	Diamond-Blackfan anemia	2014-09-25	criteria provided, single submitter	clinical testing	The c.60_61delCT pathogenic mutation, located in coding exon 2 of the RPL11 gene, results from a deletion of two nucleotides between nucleotide positions 60 and 61, causing a translational frameshift with a predicted alternate stop codon (p.C21Sfs*33). This pathogenic mutation was first described in an individual with Diamond-Blackfan anemia with a ventricular septal defect (VSD) and a narrow pulmonary artery who was responsive to steroid therapy; the proband's mother and maternal grandmother also carried the mutation and had triphalangeal thumbs (Gazda HT et al. Am J Hum Genet. 2008;83(6):769-80). Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294).
PreventionGenetics, part of Exact Sciences	RCV003415663	SCV004106986	pathogenic	RPL11-related disorder	2023-07-14	criteria provided, single submitter	clinical testing	The RPL11 c.60_61delCT variant is predicted to result in a frameshift and premature protein termination (p.Cys21Serfs*33). This variant has been reported in individuals with Diamond-Blackfan anaemia (Gazda et al. 2008. PubMed ID: 19061985; Muramatsu et al. 2017. PubMed ID: 28102861; Gálvez et al. 2021. PubMed ID: 33718801). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in RPL11 are expected to be pathogenic. This variant is interpreted as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002354149	SCV004291755	pathogenic	Diamond-Blackfan anemia	2023-08-10	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Cys21Serfs*33) in the RPL11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPL11 are known to be pathogenic (PMID: 19061985, 19773262). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 19061985, 28102861). This variant is also known as c.58_59delCT. ClinVar contains an entry for this variant (Variation ID: 5752). For these reasons, this variant has been classified as Pathogenic.
OMIM	RCV000006108	SCV000026290	pathogenic	Diamond-Blackfan anemia 7	2008-12-01	no assertion criteria provided	literature only