Submissions for variant NM_003680.4(YARS1):c.1099C>T (p.Arg367Trp)

gnomAD frequency: 0.00003  dbSNP: rs376054085

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000687751	SCV000815337	pathogenic	Charcot-Marie-Tooth disease dominant intermediate C	2024-12-16	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 367 of the YARS protein (p.Arg367Trp). This variant is present in population databases (rs376054085, gnomAD 0.03%). This missense change has been observed in individuals with autosomal recessive YARS-related conditions (PMID: 29302074, 31130284, 34536092). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 567612). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on YARS protein function. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001264808	SCV001442999	pathogenic	recessive ARS-related multisystem disease	2020-06-01	criteria provided, single submitter	clinical testing	PS1, PM2, PM3, PP1_Strong, PP3
GeneDx	RCV001584557	SCV001812954	likely pathogenic	not provided	2024-05-15	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29302074, 31130284, 16429158, 34536092, 38125821)
Athena Diagnostics	RCV001584557	SCV001879895	pathogenic	not provided	2024-06-10	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population is consistent with pathogenicity (http://gnomad.broadinstitute.org). Computational tools predict that this variant is damaging. This variant has been identified in at least one individual with clinical features associated with this gene. This variant segregates with disease in multiple families with infantile-onset multisystem neurologic, endocrine, and pancreatic disease.
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV002226737	SCV002505683	pathogenic	Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2	2022-05-03	criteria provided, single submitter	clinical testing
Juno Genomics, Hangzhou Juno Genomics, Inc	RCV002226737	SCV005418633	likely pathogenic	Neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 2		criteria provided, single submitter	clinical testing	PM2_Supporting+PM3+PP1_Strong+PP3