Submissions for variant NM_001022.4(RPS19):c.3G>T (p.Met1Ile)

dbSNP: rs138938035

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413436	SCV000490777	pathogenic	not provided	2021-01-04	criteria provided, single submitter	clinical testing	Observed in an additional unrelated patient in published literature with DBA (Ramenghi et al., 2000); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 15059149, 11112378, 28376382)
Ambry Genetics	RCV002374616	SCV002625331	pathogenic	Diamond-Blackfan anemia	2016-08-23	criteria provided, single submitter	clinical testing	The p.M1? pathogenic mutation (also known as c.3G>T) is located in coding exon 1 of the RPS19 gene and results from a G to T substitution at nucleotide position 3. This alters the methionine residue at the initiation codon. This mutation was reported as a de novo occurrence in an infant with a clinical diagnosis of Diamond-Blackfan Anemia (DBA); malformations were reportedly absent and the patient did not respond to steroids. The same study described another affected individual with a mutation at the same codon (c.3G>C) (Ramenghi U et al. Blood Cells Mol. Dis., 2000 Oct;26:417-22). This mutation was later reported in another infant with DBA who presented with symptoms at 6 weeks of age. This patient did not have malformations but did respond to steroids (Orfali et al. Br J Haematol. 2004;125(2):243-252:). 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002374616	SCV003443257	pathogenic	Diamond-Blackfan anemia	2023-02-04	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). This sequence change affects the initiator methionine of the RPS19 mRNA. The next in-frame methionine is located at codon 75. Disruption of the initiator codon has been observed in individuals with Diamond-Blackfan anemia or clinical features of this condition (PMID: 11112378, 24675553, 27329125, 28376382). This variant is also known as nt3 G->C. ClinVar contains an entry for this variant (Variation ID: 372494). For these reasons, this variant has been classified as Pathogenic.
Medical Genetics Center, Maternal and Child Health Hospital of Hubei Province	RCV003168598	SCV003915605	pathogenic	Diamond-Blackfan anemia 1	2022-08-01	criteria provided, single submitter	clinical testing