ClinVar Miner

Submissions for variant NM_015166.3(MLC1):c.65G>A (p.Arg22Gln) (rs184241759)

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Total submissions: 6
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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
Illumina Clinical Services Laboratory,Illumina RCV000490481 SCV000915977 likely pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 1 2018-10-18 criteria provided, single submitter clinical testing The MLC1 c.65G>A (p.Arg22Gln) missense variant has been reported in a compound heterozygous state with a second missense variant in a total of four individuals, including two siblings, with megalencephalic leukoencephalopathy with subcortical cysts (Wang et al. (2011). The p.Arg22Gln variant was absent from 170 control samples and is reported at a frequency of 0.004565 in the East Asian population of the Genome Aggregation Database. Xie et al. (2012) performed functional studies and found that the p.Arg22Gln variant inhibited MLC1 protein function in the cell membrane by trapping the protein in the endoplasmic reticulum. Based on the evidence, the p.Arg22Gln 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.
Baylor Genetics RCV000490481 SCV001163452 likely pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 1 criteria provided, single submitter clinical testing
Natera, Inc. RCV001272318 SCV001454193 uncertain significance Megalencephalic leukoencephalopathy with subcortical cysts 2020-01-06 no assertion criteria provided clinical testing

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