Submissions for variant NM_001022.4(RPS19):c.406G>T (p.Gly136Ter)

dbSNP: rs144337183

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000414046	SCV000490778	pathogenic	not provided	2015-07-10	criteria provided, single submitter	clinical testing	The G136X nonsense variant in the RPS19 gene is predicted to cause loss of normal protein function throughprotein truncation. Although this variant has not been reported previously to our knowledge, we interpret it as pathogenic.
Ambry Genetics	RCV002323577	SCV002627257	pathogenic	Diamond-Blackfan anemia	2017-05-31	criteria provided, single submitter	clinical testing	The p.G136* pathogenic mutation (also known as c.406G>T), located in coding exon 4 of the RPS19 gene, results from a G to T substitution at nucleotide position 406. This changes the amino acid from a glycine to a stop codon within coding exon 4. This mutation was identified an individual with Diamond-Blackfan anemia (Smetanina NS et al. Pediatr Blood Cancer, 2015 Sep;62:1597-600). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation. As such, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV002323577	SCV004298399	pathogenic	Diamond-Blackfan anemia	2023-03-30	criteria provided, single submitter	clinical testing	Experimental studies have shown that this premature translational stop signal affects RPS19 function (PMID: 29766597). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the RPS19 protein in which other variant(s) (p.Gln137*) have been observed in individuals with RPS19-related conditions (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. ClinVar contains an entry for this variant (Variation ID: 372495). This premature translational stop signal has been observed in individual(s) with Diamond-Blackfan anemia (PMID: 25946618; Invitae). 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.Gly136*) in the RPS19 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 10 amino acid(s) of the RPS19 protein.