Total submissions: 11
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Illumina Laboratory Services, |
RCV000004984 | SCV000439243 | likely pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 2017-04-27 | criteria provided, single submitter | clinical testing | The MLC1 c.274C>T (p.Pro92Ser) missense variant has been identified in a compound heterozygous state in at least three individuals with megalencephalic leukoencephalopathy, in a heterozygous state in two affected individuals in whom a second variant was not identified, and in one affected individual in whom a second variant was found but zygosity was not confirmed (Leegwater et al. 2002; Ben-Zeev et al. 2002; Montagna et al. 2006; Yuzbasioglu et al. 2011). The p.Pro92Ser variant was absent from 240 control alleles and is reported at a frequency of 0.00037 in the European (non-Finnish) population of the Exome Aggregation Consortium. Functional studies using HeLa and COS cells demonstrated reduced surface expression of the p.Pro92Ser-MLC1 protein compared to wild type. The variant protein was confined to late endosomes/lysosomes instead of recycling endosomes (Duarri et al. 2008). Based on the evidence, the p.Pro92Ser variant is classified as likely pathogenic for megalencephalic leukoencephalopathy with subcortical cysts. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. |
| Counsyl | RCV000004984 | SCV000485560 | likely pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 2016-01-08 | criteria provided, single submitter | clinical testing | |
| Baylor Genetics | RCV000004984 | SCV001529596 | pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 2024-03-29 | criteria provided, single submitter | clinical testing | |
| Labcorp Genetics |
RCV001378687 | SCV001576310 | likely pathogenic | not provided | 2024-01-14 | criteria provided, single submitter | clinical testing | This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 92 of the MLC1 protein (p.Pro92Ser). This variant is present in population databases (rs121908345, gnomAD 0.2%). This missense change has been observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 11935341, 16470554, 21145992). ClinVar contains an entry for this variant (Variation ID: 4719). Advanced 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 at Invitae 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 MLC1 protein function. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 23793458). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001844006 | SCV002103896 | pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts | 2022-02-24 | criteria provided, single submitter | clinical testing | Variant summary: MLC1 c.274C>T (p.Pro92Ser) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 232710 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in MLC1 causing Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (0.00013 vs 0.0011), allowing no conclusion about variant significance. c.274C>T has been reported in the literature in multiple individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (example, Leegwater_2002, Ben-Zeev_2002, Montagna_2006). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (example Duarri_2008). The most pronounced variant effect results in localization within the lysosomes after internalization from the plasma membrane. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Fulgent Genetics, |
RCV000004984 | SCV002813874 | likely pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 2024-04-11 | criteria provided, single submitter | clinical testing | |
| Greenwood Genetic Center Diagnostic Laboratories, |
RCV000004984 | SCV003798989 | likely pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 2022-10-03 | criteria provided, single submitter | clinical testing | PS3, PM2, PP3 |
| Ce |
RCV001378687 | SCV004153338 | likely pathogenic | not provided | 2023-10-01 | criteria provided, single submitter | clinical testing | MLC1: PM2, PM3, PM5, PP4, PS3:Supporting |
| Institute of Human Genetics, |
RCV000004984 | SCV004801424 | pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 2024-03-19 | criteria provided, single submitter | clinical testing | This variant has been identified by standard clinical testing. in trans with MLC1 (NM_015166.4): c.423+1G>T |
| Mayo Clinic Laboratories, |
RCV001378687 | SCV005413413 | likely pathogenic | not provided | 2023-12-07 | criteria provided, single submitter | clinical testing | PP3, PM2_moderate, PS3_moderate, PS4_moderate |
| OMIM | RCV000004984 | SCV000025160 | pathogenic | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 2002-08-01 | no assertion criteria provided | literature only |