Submissions for variant NM_020117.11(LARS1):c.3313C>T (p.Arg1105Ter)

gnomAD frequency: 0.00006  dbSNP: rs369437593

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV000762168	SCV000892433	likely pathogenic	not provided	2018-05-01	criteria provided, single submitter	clinical testing
Institute of Human Genetics, University of Leipzig Medical Center	RCV001723769	SCV001950037	pathogenic	Infantile liver failure syndrome 1	2021-08-03	criteria provided, single submitter	clinical testing	This variant was identified as homozygous.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000762168	SCV002011527	pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002469057	SCV002766413	pathogenic	Acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins	2022-11-04	criteria provided, single submitter	clinical testing	Variant summary: LARS c.3313C>T (p.Arg1105X) results in a premature termination codon, predicted to cause a truncation of the encoded protein. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 2e-05 in 250994 control chromosomes (gnomAD). c.3313C>T has been reported in the literature as a homozygous genotype in two siblings affected with Liver Failure Acute Infantile, Type 1 (e.g. Lenz_2020). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact of the variant on protein function in fibroblasts derived from a homozygous patient (e.g. Lenz_2020). The variant resulted in a truncated protein product but did not appear to undergo nonsense mediated decay. The protein showed reduced enzymatic activity, approximately 70% of normal, which was further reduced at higher temperatures to approximately 45% of normal, likely as a result of reduced protein stability, as indicated by a reduced expression at higher temperatures evaluated by western blotting. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as either pathogenic (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic.
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335191	SCV004046241	likely pathogenic	LARS1-Related Disorder		criteria provided, single submitter	clinical testing	This nonsense variant found in exon 31 of 32 is predicted to result in protein truncation. This variant has been previously reported as a homozygous change in two related individuals with features of infantile liver failure syndrome 1 (ILFS1), however both were noted to lack the episodic liver dysfunction that is typical of the disorder (PMID: 32699352). Experimental studies have shown that the presence of the c.3313C>T (p.Arg1105Ter) variant leads to reduced LARS1 enzyme activity, and that the variant likely causes truncation of the LARS1 protein (PMID: 32699352). The c.3313C>T (p.Arg1105Ter) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002479% (7/282358) and is absent in the homozygous state. Based on the available evidence, the c.3313C>T (p.Arg1105Ter) variant is classified as Likely Pathogenic.