Submissions for variant NM_015166.4(MLC1):c.65G>A (p.Arg22Gln)

gnomAD frequency: 0.00011  dbSNP: rs184241759

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	RCV000490481	SCV000267394	uncertain significance	Megalencephalic leukoencephalopathy with subcortical cysts 1	2016-03-18	criteria provided, single submitter	reference population
GeneDx	RCV000479932	SCV000565135	uncertain significance	not provided	2017-02-10	criteria provided, single submitter	clinical testing	The R22Q variant in the MLC1 gene has been reported previously in a patient with megalencephalic leukoencephalopathy with subcortical cysts, however, this patient was not found to have a pathogenic variant on the other MLC1 allele (Wang et al., 2011). The R22Q variant is observed in 43/8556 (0.5%) alleles from individuals of East Asian background, in the ExAC dataset (Lek et al., 2016). The R22Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. While transfection studies indicate that the R22Q variant affected intracellular protein localization, protein/mRNA expression levels for R22Q were comparable with wild type (Xie et al., 2012). Therefore, we interpret R22Q as a variant of uncertain significance.
Counsyl	RCV000490481	SCV000792523	uncertain significance	Megalencephalic leukoencephalopathy with subcortical cysts 1	2017-06-29	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV000490481	SCV001163452	uncertain significance	Megalencephalic leukoencephalopathy with subcortical cysts 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002222445	SCV002500330	uncertain significance	not specified	2022-09-14	criteria provided, single submitter	clinical testing	Variant summary: MLC1 c.65G>A (p.Arg22Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00047 in 250418 control chromosomes (gnomAD), predominantly at a frequency of 0.0044 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in MLC1 causing Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.65G>A has been reported in the literature in individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1, including one sibling pair that carried a second pathogenic variant in trans (Wang_2011). The variant was also found in one affected individual with a benign variant on the second allele (Wang_2011) and in one individual that carried a likely pathogenic variant in cis and another potentially pathogenic variant (c.772-1G>C) in trans (Cao_2016). These data indicate that the variant may be associated with disease. One functional study demonstrated that the variant protein is mislocalized in the cell, with 8.26% of the protein being trafficked to the cell surface, and the remainder being trapped in the endoplasmic reticulum (Xie_2012). Five ClinVar submitters have assessed the variant since 2014: four classified the variant as of uncertain significance, and one as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000479932	SCV003291648	uncertain significance	not provided	2022-07-12	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 22 of the MLC1 protein (p.Arg22Gln). This variant is present in population databases (rs184241759, gnomAD 0.5%). This missense change has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 21160490). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 225412). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects MLC1 function (PMID: 22416245). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Natera, Inc.	RCV001272318	SCV001454193	uncertain significance	Megalencephalic leukoencephalopathy with subcortical cysts	2020-01-06	no assertion criteria provided	clinical testing