Submissions for variant NM_000969.5(RPL5):c.169_172del (p.Asn57fs)

dbSNP: rs1558284033

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000702906	SCV000831781	pathogenic	Diamond-Blackfan anemia	2022-02-21	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 579583). This variant is also known as 166_169del (56_57del). This premature translational stop signal has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 19061985, 19773262, 20960466, 23718193). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Asn57Glufs*12) in the RPL5 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RPL5 are known to be pathogenic (PMID: 19061985, 19773262).
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000761557	SCV000889935	pathogenic	Diamond-Blackfan anemia 1	2019-03-13	criteria provided, single submitter	clinical testing	The p.N57Qfs*12 variant in the RPL5 gene is a de novo frameshift variant, which is absent in the gnomAD database and has previously been reported as a pathogenic variant in the ClinVar database (Accession: RCV000702906.1). In summary, the p.N57Qfs*12 variant meets the ACMG criteria to be classified as pathogenic based upon inheritance model, absence from controls and previous ClinVar submission.
GeneDx	RCV001008074	SCV001167812	pathogenic	not provided	2019-02-04	criteria provided, single submitter	clinical testing	The c.169_172delAACA variant has been reported previously in association with Diamond-Blackfan anemia, including an apparently de novo occurrence (Cmejla et al., 2009; Quarello et al., 2010; Gerrard et al., 2013). The deletion causes a frameshift starting with codon Asparagine 57, changes this amino acid to a Glutamic acid residue and creates a premature Stop codon at position 12 of the new reading frame, denoted p.Asn57GlufsX12. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is not observed in large population cohorts (Lek et al., 2016). In summary, we consider the variant to be pathogenic.
CeGaT Center for Human Genetics Tuebingen	RCV001008074	SCV001245631	pathogenic	not provided	2018-06-01	criteria provided, single submitter	clinical testing
Mendelics	RCV002249419	SCV002518994	pathogenic	Diamond-Blackfan anemia 6	2022-05-04	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000702906	SCV002710870	pathogenic	Diamond-Blackfan anemia	2015-09-04	criteria provided, single submitter	clinical testing	The c.169_172delAACA pathogenic mutation, located in coding exon 3 of the RPL5 gene, results from a deletion of 4 nucleotides between nucleotide positions 169 and 172, causing a translational frameshift with a predicted alternate stop codon. This mutation has been reported as a sporadic or de novo occurrence in multiple DBA patients with associated congenital anomalies. One individual, diagnosed at birth, was reported to have partial anomalous pulmonary venous return and to be unresponsive to steroid therapy (Gazda HT, Am. J. Hum. Genet. 2008 Dec; 83(6):769-80). A patient with flat thenar eminence, grouped carpal bones, and short stature, and another with intellectual disability, myelomeningocele, cleft palate, and facial dysmorphism, have been reported (Quarello P, Haematologica 2010 Feb; 95(2):206-13; Boria I, Hum. Mutat. 2010 Dec; 31(12):1269-79). In a cohort of Czech DBA patients, an individual small for gestational age with flat thenar and facial dysmorphism was described (Cmejla R, Hum. Mutat. 2009 Mar; 30(3):321-7). In addition to the clinical data presented in the literature, since premature stop codons 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).
Eurofins-Biomnis	RCV002249419	SCV003935092	pathogenic	Diamond-Blackfan anemia 6	2022-09-23	criteria provided, single submitter	clinical testing