ClinVar Miner

Submissions for variant NM_015166.4(MLC1):c.908_918delinsGCA (p.Val303fs)

dbSNP: rs2146772952
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV003101602 SCV003613388 pathogenic Inborn genetic diseases 2022-03-22 criteria provided, single submitter clinical testing The c.908_918delTGCTGCTGCTGinsGCA (p.V303Gfs*96) alteration, located in exon 11 (coding exon 10) of the MLC1 gene, consists of a deletion of 11 and insertion of 3 nucleotides causing a translational frameshift at position 908 with a predicted alternate stop codon after 96 amino acids. This alteration occurs at the 3' terminus of the MLC1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 20% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been detected in the homozygous state, and in conjunction with another MLC1 alteration, in multiple individuals with megalencephalic leukoencephalopathy with subcortical cysts (Abdel-Salam, 2016; Mahmoud, 2014; Broová, 2019; Leegwater, 2001). Based on the available evidence, this alteration is classified as pathogenic.
Baylor Genetics RCV002279181 SCV004194968 pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 1 2023-11-11 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002279181 SCV005663894 pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 1 2024-03-15 criteria provided, single submitter clinical testing
3billion RCV002279181 SCV005905219 pathogenic Megalencephalic leukoencephalopathy with subcortical cysts 1 2024-03-14 criteria provided, single submitter clinical testing The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with MLC1 related disorder (ClinVar ID: VCV001071728 /3billion dataset). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
GeneReviews RCV002279181 SCV002567813 not provided Megalencephalic leukoencephalopathy with subcortical cysts 1 no assertion provided literature only

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