Submissions for variant NM_015166.4(MLC1):c.634G>A (p.Gly212Arg)

dbSNP: rs281875317

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000412227	SCV000486687	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2016-07-22	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000059746	SCV001398511	pathogenic	not provided	2022-06-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly212 amino acid residue in MLC1. Other variant(s) that disrupt this residue have been observed in individuals with MLC1-related conditions (PMID: 11254442, 11935341, 21145992, 27322623), which suggests that this may be a clinically significant amino acid residue. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. Studies have shown that this missense change alters MLC1 gene expression (PMID: 18757878). 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) performed at Invitae indicates that this missense variant is expected to disrupt MLC1 protein function. ClinVar contains an entry for this variant (Variation ID: 68794). This missense change has been observed in individuals with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 11254442, 21145992, 27322623). This variant is present in population databases (rs281875317, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 212 of the MLC1 protein (p.Gly212Arg).
3billion	RCV000412227	SCV002318592	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2022-03-22	criteria provided, single submitter	clinical testing	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000068794,VCV000553381, PMID:11254442). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 11254442, 21145992, 27322623). Functional assays showed that the variant had moderate level of impact on gene/protein function (PMID: 15367490, 18757878). Different pathogenic/likely pathogenic amino acid change has been reported with supporting evidence at the same codon (PMID:11935341). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.902>=0.6, 3CNET: 0.797>=0.75). The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000040). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235028	SCV003933927	likely pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts	2023-05-05	criteria provided, single submitter	clinical testing	Variant summary: MLC1 c.634G>A (p.Gly212Arg) 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 4e-06 in 250780 control chromosomes. c.634G>A has been reported in the literature in homozygous and compound heterozygous individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (Leegwater_2001, Yuzbasioglu_2011, Cao_2016) with second reported alleles both pathogenic and uncertain significance. These data indicate that the variant is likely to be associated with disease. One publication reports experimental evidence showing severely reduced (<10% WT levels) presence of the protein at the plasma membrane, however, does not allow convincing conclusions about the variant effect (Duarri_2008). The following publications have been ascertained in the context of this evaluation (PMID: 27322623, 18757878, 11254442, 21145992). Three 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 pathogenic (n=2) or likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000412227	SCV004242415	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2024-01-02	criteria provided, single submitter	clinical testing	Criteria applied: PS1,PS3,PM3,PM5,PM2_SUP,PP4
Rare Genetic Disease Lab, Dept of Zoology, Government Postgraduate College Dargai Malakand, Higher Education Govt. of Khyber Pakhtunkhwa	RCV000412227	SCV005038954	pathogenic	Megalencephalic leukoencephalopathy with subcortical cysts 1	2022-12-06	criteria provided, single submitter	research
UniProtKB/Swiss-Prot	RCV000059746	SCV000091316	not provided	not provided		no assertion provided	not provided