Submissions for variant NM_001040436.3(YARS2):c.98C>A (p.Ser33Ter)

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003087396	SCV003472652	pathogenic	not provided	2022-11-01	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This premature translational stop signal has been observed in individual(s) with sideroblastic anemia (PMID: 30026338). This variant is present in population databases (rs748941040, gnomAD 0.004%). This sequence change creates a premature translational stop signal (p.Ser33*) in the YARS2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in YARS2 are known to be pathogenic (PMID: 20598274, 24344687, 25638461).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003404069	SCV004122489	pathogenic	Myopathy, lactic acidosis, and sideroblastic anemia 2	2023-09-13	criteria provided, single submitter	clinical testing	Variant summary: YARS2 c.98C>A (p.Ser33X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 2e-05 in 250752 control chromosomes. c.98C>A has been reported in the literature in individuals affected with Myopathy, Lactic Acidosis, And Sideroblastic Anemia 2 (e.g. Rudaks_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 35393742). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
GeneDx	RCV003087396	SCV005327582	pathogenic	not provided	2023-04-12	criteria provided, single submitter	clinical testing	Nonsense variant predicted to result in protein truncation or nonsense mediated decay 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: 35641312, 30026338, 35393742)