Submissions for variant NM_005051.3(QARS1):c.1284_1285del (p.Asp430fs)

gnomAD frequency: 0.00003  dbSNP: rs775652214

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003333093	SCV002247245	pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2024-11-15	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp430Glnfs*16) in the QARS gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in QARS are known to be pathogenic (PMID: 24656866, 25471517). This variant is present in population databases (rs775652214, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with QARS-related conditions. ClinVar contains an entry for this variant (Variation ID: 544132). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002534224	SCV003759041	pathogenic	Inborn genetic diseases	2021-09-05	criteria provided, single submitter	clinical testing	The c.1284_1285delAG (p.D430Qfs*16) alteration, located in exon 14 (coding exon 14) of the QARS gene, consists of a deletion of 2 nucleotides from position 1284 to 1285, causing a translational frameshift with a predicted alternate stop codon after 16 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on the available evidence, this alteration is classified as pathogenic.
GeneDx	RCV001855342	SCV004025607	uncertain significance	not provided	2025-01-02	criteria provided, single submitter	clinical testing	Frameshift 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; Reported as a single heterozygous variant in two probands with epilepsy; a second variant in this gene was not identified (PMID: 31440721); This variant is associated with the following publications: (PMID: 33256324, 31440721)
Baylor Genetics	RCV003333093	SCV004041223	likely pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2023-01-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003333093	SCV005394034	pathogenic	Diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome	2024-09-04	criteria provided, single submitter	clinical testing	Variant summary: QARS1 c.1284_1285delAG (p.Asp430GlnfsX16) 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 1.9e-05 in 1614088 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in QARS1 causing Diffuse Cerebral And Cerebellar Atrophy-Intractable Seizures-Progressive Microcephaly Syndrome, allowing no conclusion about variant significance. c.1284_1285delAG has been reported in the literature in at-least one individual affected with Glutaminyl-tRNA synthetase deficiency (example: Shen_2020). The following publication has been ascertained in the context of this evaluation (PMID: 33256324). ClinVar contains an entry for this variant (Variation ID: 544132). Based on the evidence outlined above, the variant was classified as pathogenic.