22-50064163-T-TAGC
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP3
The NM_015166.4(MLC1):c.927_929dupGCT(p.Leu310dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000299 in 1,604,634 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000031 ( 0 hom. )
Consequence
MLC1
NM_015166.4 disruptive_inframe_insertion
NM_015166.4 disruptive_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.94
Genes affected
MLC1 (HGNC:17082): (modulator of VRAC current 1) The function of this gene product is unknown; however, homology to other proteins suggests that it may be an integral membrane transporter. Mutations in this gene have been associated with megalencephalic leukoencephalopathy with subcortical cysts, an autosomal recessive neurological disorder. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP3
Nonframeshift variant in repetitive region in NM_015166.4
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MLC1 | NM_015166.4 | c.927_929dupGCT | p.Leu310dup | disruptive_inframe_insertion | 11/12 | ENST00000311597.10 | NP_055981.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
MLC1 | ENST00000311597.10 | c.927_929dupGCT | p.Leu310dup | disruptive_inframe_insertion | 11/12 | 1 | NM_015166.4 | ENSP00000310375.6 | ||
MLC1 | ENST00000395876.6 | c.927_929dupGCT | p.Leu310dup | disruptive_inframe_insertion | 11/12 | 1 | ENSP00000379216.2 | |||
MLC1 | ENST00000483836.1 | n.284_286dupGCT | non_coding_transcript_exon_variant | 4/5 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 151914Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000557 AC: 13AN: 233570Hom.: 0 AF XY: 0.0000704 AC XY: 9AN XY: 127780
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GnomAD4 exome AF: 0.0000310 AC: 45AN: 1452604Hom.: 0 Cov.: 39 AF XY: 0.0000374 AC XY: 27AN XY: 722834
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152030Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Megalencephalic leukoencephalopathy with subcortical cysts 1 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 09, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 21, 2017 | The MLC1 c.927_929dupGCT (p.Leu310dup) in-frame insertion variant has been reported in one study and is found in a compound heterozygous state with a frameshift variant in one individual with megalencephalic leukoencephalopathy with subcortical cysts (Montagna et al. 2006). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Montagna et al. (2006) performed functional studies of the p.Leu310dup variant expressed in Xenopus oocytes and found that protein expression was reduced by 55% compared to wild type and plasma membrane expression decreased by 65% compared to wild type. Based on the evidence, the p.Leu310dup variant is classified as a variant of unknown significance but suspicious for pathogenicity for megalencephalic leukoencephalopathy with subcortical cysts. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 12, 2023 | Variant summary: MLC1 c.927_929dupGCT (p.Leu310dup) results in an in-frame duplication that is predicted to duplicate one amino acid into the encoded protein. The variant allele was found at a frequency of 5.6e-05 in 233570 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in MLC1 causing Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (5.6e-05 vs 0.0011), allowing no conclusion about variant significance. c.927_929dupGCT has been reported in the literature in at-least one individual affected with milder features of Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (example, Montagna_2006 cited in van der Knaap_2012 and Capdevila-Nortes_2013). These report(s) do not provide unequivocal conclusions about association of the variant with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1. At least one publication reports experimental evidence evaluating an impact on protein function (Montagna_2006). The most pronounced variant effect results in >50%-90% of normal protein and plasma membrane expression. The following publications have been ascertained in the context of this evaluation (PMID: 23793458, 16470554, 23079554). Three submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 10, 2022 | This variant, c.927_929dup, results in the insertion of 1 amino acid(s) of the MLC1 protein (p.Leu310dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 16470554). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects MLC1 function (PMID: 16470554, 23793458). 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. - |
Computational scores
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Name
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Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at