ClinVar Miner

Submissions for variant NM_001029.5(RPS26):c.1A>G (p.Met1Val)

dbSNP: rs143951267
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000006496 SCV000768797 pathogenic Diamond-Blackfan anemia 10 2023-02-17 criteria provided, single submitter clinical testing This sequence change affects the initiator methionine of the RPS26 mRNA. The next in-frame methionine is located at codon 115. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 20116044, 24942156, 26136524). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 6122). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV002415402 SCV002720189 pathogenic Diamond-Blackfan anemia 2017-12-22 criteria provided, single submitter clinical testing The p.M1? pathogenic mutation (also known as c.1A>G) is located in coding exon 1 of the RPS26 gene and results from an A to G substitution at nucleotide position 1. This alters the methionine residue at the initiation codon. This pathogenic mutation was first described in 4 individuals and 2 additional family members who were affected with Diamond-Blackfan anemia (Doherty L et al. Am. J. Hum. Genet., 2010 Feb;86:222-8). In addition to the clinical data presented in the literature, since sequence variations that modify the initiation codon (ATG) are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame, this alteration is interpreted as a disease-causing mutation.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard RCV000006496 SCV003761420 pathogenic Diamond-Blackfan anemia 10 2023-01-25 criteria provided, single submitter curation The heterozygous p.Met1Val variant in RPS26 was identified by our study in one individual with Diamond-Blackfan anemia. The p.Met1Val variant in RPS26 has been reported in 8 unrelated individuals with Diamond-Blackfan anemia 10 (PMID: 26136524, PMID: 20116044, PMID: 24942156) and segregated with disease in 4 affected relatives from 2 families (PMID: 20116044). The number of reported affected individuals with this variant is greater than expected compared to non-affected individuals with this variant. This variant was found to be de novo in 4 individuals with confirmed paternity and maternity (PMID: 24942156, PMID: 20116044). This variant has also been reported in ClinVar (Variation ID: 6122) and has been interpreted as pathogenic by OMIM, Invitae, and Ambry Genetics. Four pathogenic or likely pathogenic variants, resulting in a different amino acid change at the same position, c.1A>C (p.Met1Leu), c.1A>T (p.Met1Leu), c.2T>C (p.Met1Thr), and c.2T>G (p.Met1Arg), have been reported in ClinVar, supporting that a change at this position may not be tolerated (ClinVar Variation ID: 598993, 6123, 1798678, 933891). This variant was absent from large population studies. This variant is located in the first amino acid and obliterates the methionine initiation codon. The next in-frame methionine is at amino acid residue 115 and there are 19 reported pathogenic or likely pathogenic variants in ClinVar upstream of this downstream methionine. 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_Moderate, PS2, PS4, PM2_Supporting, PP1 (Richards 2015).
Revvity Omics, Revvity RCV000006496 SCV003827226 pathogenic Diamond-Blackfan anemia 10 2023-06-16 criteria provided, single submitter clinical testing
GeneDx RCV003225019 SCV003921563 pathogenic not provided 2023-04-24 criteria provided, single submitter clinical testing Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28102861, 25525159, 28280134, 33718801, 20116044)
OMIM RCV000006496 SCV000026679 pathogenic Diamond-Blackfan anemia 10 2010-02-12 no assertion criteria provided literature only

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