ClinVar Miner

Submissions for variant NM_015166.4(MLC1):c.973C>T (p.Gln325Ter)

gnomAD frequency: 0.00001  dbSNP: rs1057516465
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000409034 SCV000485720 likely pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 1 2016-02-02 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001861366 SCV002151416 pathogenic not provided 2022-07-04 criteria provided, single submitter clinical testing For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 370408). This variant has not been reported in the literature in individuals affected with MLC1-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.008%). This sequence change creates a premature translational stop signal (p.Gln325*) in the MLC1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MLC1 are known to be pathogenic (PMID: 11254442, 16470554, 24824219).
Baylor Genetics RCV000409034 SCV004194998 likely pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 1 2023-04-10 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV004017600 SCV004847420 likely pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 2024-01-29 criteria provided, single submitter clinical testing The p.Gln325X variant in MLC1 has not been previously reported in individuals with megalencephalic leukoencephalopathy but has been reported by other clinical laboratories in ClinVar (Variation ID 370408). It has also been identified in 0.002% (1/41410) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). This nonsense variant leads to a premature termination codon at position 325, which is predicted to lead to a truncated or absent protein. Biallelic loss of function of the MLC1 gene is an established disease mechanism in autosomal recessive megalencephalic leukoencephalopathy. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal recessive megalencephalic leukoencephalopathy. ACMG/AMP Criteria applied: PVS1, PM2_Supporting.

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