Total submissions: 10
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Centre for Mendelian Genomics, |
RCV000256219 | SCV001369637 | likely pathogenic | Hypomyelinating leukodystrophy 9 | 2020-03-13 | criteria provided, single submitter | clinical testing | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3_MOD,PS4_MOD,PM3,PP3. |
Ce |
RCV001532053 | SCV001747435 | likely pathogenic | not provided | 2022-01-01 | criteria provided, single submitter | clinical testing | |
Institute for Clinical Genetics, |
RCV001532053 | SCV002010047 | pathogenic | not provided | 2021-11-03 | criteria provided, single submitter | clinical testing | |
3billion | RCV000256219 | SCV002318718 | likely pathogenic | Hypomyelinating leukodystrophy 9 | 2022-03-22 | criteria provided, single submitter | clinical testing | Same or different nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000265854, PMID:28905880). In silico tool predictions suggest damaging effect of the variant on gene or gene product(3CNET: 0.777>=0.75). A missense variant is a common mechanism associated with Leukodystrophy, hypomyelinating, 9. The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0005004). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. |
Invitae | RCV001532053 | SCV002508094 | benign | not provided | 2024-01-02 | criteria provided, single submitter | clinical testing | |
Genetics and Molecular Pathology, |
RCV000256219 | SCV002556868 | likely pathogenic | Hypomyelinating leukodystrophy 9 | 2021-04-15 | criteria provided, single submitter | clinical testing | |
Victorian Clinical Genetics Services, |
RCV000256219 | SCV002557765 | likely pathogenic | Hypomyelinating leukodystrophy 9 | 2022-06-24 | criteria provided, single submitter | clinical testing | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0102 - Loss of function is a likely mechanism of disease in this gene and is associated with hypomyelinating leukodystrophy, 9 (MIM#616140). Toxic gain of function has also been suggested (PMID: 31737794). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from serine to leucine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (119 heterozygotes, 2 homozygotes). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located adjacent in the annotated KMSKS motif, near a catalytic domain (PMID: 33515434, PMID: 28905880). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as likely pathogenic and pathogenic, and observed in two compound heterozygous individuals with a hypomyelination disorder or mild hypomyelinating leukodystrophy. In one individual, the second variant was either due to a de novo event or non-paternity (PMID: 28905880, PMID: 31814314, ClinVar). (SP) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells demonstrated protein mislocalization, increases in punctate structures and decreased phosphorylation of ribosomal S6 protein (PMID: 31737794), whereas transfected E.coli cells showed decreased aminoacetylation activity (PMID: 33515434). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV000256219 | SCV004037846 | likely pathogenic | Hypomyelinating leukodystrophy 9 | 2023-06-14 | criteria provided, single submitter | clinical testing | Variant summary: RARS c.1367C>T (p.Ser456Leu) results in a non-conservative amino acid change located in the Arginyl-tRNA synthetase, catalytic core domain (IPR035684) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00038 in 244948 control chromosomes in the gnomAD database, including 2 homozygotes. c.1367C>T has been reported in the literature in compound heterozygous individuals affected with PelizaeusMerzbacher disease (Nafinisia_2017) or mild hypomyelinating leukodystrophy (Mendes_2020), and the former had a truncating variant in trans. These data indicate that the variant is likely associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that the variant results in reduced aminoacylation activity and phosphorylation of ribosomal S6 protein, as well as disrupting protein localization and formation of myelin structures (Matsumoto_2019, Li_2021). The following publications have been ascertained in the context of this evaluation (PMID: 28905880, 31814314, 33515434, 31737794). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic/likely pathogenic (n=7) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. |
Baylor- |
RCV000256219 | SCV000322810 | pathogenic | Hypomyelinating leukodystrophy 9 | no assertion criteria provided | research | ||
OMIM | RCV000256219 | SCV000851997 | pathogenic | Hypomyelinating leukodystrophy 9 | 2019-08-20 | no assertion criteria provided | literature only |