Submissions for variant NM_024537.4(CARS2):c.655G>A (p.Ala219Thr)

gnomAD frequency: 0.00001  dbSNP: rs727505361

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000494053	SCV000582198	likely pathogenic	not provided	2024-02-12	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Messenger RNA studies show the variant leads to loss of exon 6 resulting in an in frame deletion of 28 amino acids belonging to a conserved surface loop of the cysteinyl-tRNA synthetase protein (PMID: 25361775); This variant is associated with the following publications: (PMID: 25361775, 37359369, 37151360, 34704010)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000156934	SCV001563239	uncertain significance	Combined oxidative phosphorylation defect type 27	2023-12-11	criteria provided, single submitter	clinical testing	This sequence change affects codon 219 of the CARS2 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the CARS2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs727505361, gnomAD 0.003%). This variant has been observed in individual(s) with CARS2-related conditions (PMID: 25361775, 34704010). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 180135). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 25361775). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Neuberg Centre For Genomic Medicine, NCGM	RCV000156934	SCV005044791	likely pathogenic	Combined oxidative phosphorylation defect type 27		criteria provided, single submitter	clinical testing	The missense c.655G>A p.Ala219Thr variant in CARS2 gene has been reported in homozygous state in multiple individuals affected with Combined oxidative phosphorylation deficiency 27 Kapoor D et al. 2021; Chen T et al. 2017; Hallmann K et al. 2014. The p.Ala219Thr variant has allele frequency 0.001% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes. This variant has been reported to the ClinVar database as Uncertain Significance / Pathogenic / Likely pathogenic.The amino acid change p.Ala219Thr in CARS2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 219 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. Functional studies are required to prove the pathogenicity for the variant, for these reasons, this variant has been classified as Likely Pathogenic.
3billion	RCV000156934	SCV005904649	likely pathogenic	Combined oxidative phosphorylation defect type 27	2023-08-14	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.001%). Predicted Consequence/Location: Missense variant Functional studies provide moderate evidence of the variant having a damaging effect on the gene or gene product (PMID: 25361775). In silico tools predict the variant to alter splicing and produce an abnormal transcript [SpliceAI: 0.92 (>=0.2, moderate evidence for spliceogenicity)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with CARS2 related disorder (ClinVar ID: VCV000180135 /PMID: 25361775 /3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 25361775). The variant has been reported to co-segregate with the disease in at least one similarly affected relative/individual in the same family or similarly affected unrelated family (PMID: 25361775). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline.
OMIM	RCV000156934	SCV000206655	pathogenic	Combined oxidative phosphorylation defect type 27	2014-12-02	no assertion criteria provided	literature only
Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa	RCV000156934	SCV003919157	likely pathogenic	Combined oxidative phosphorylation defect type 27	2023-02-06	no assertion criteria provided	clinical testing