chr22-50064163-T-TAGC

Position:

• chr22-50064163-T-TAGC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP3

The ENST00000311597.10(MLC1):​c.929_930insGCT​(p.Leu309dup) variant causes a 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L310L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000031 (0 hom.)
• Consequence: MLC1 ENST00000311597.10 inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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]

ACMG classification

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 ENST00000311597.10

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.929_930insGCT	p.Leu309dup	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.929_930insGCT	p.Leu309dup	inframe_insertion	11/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.929_930insGCT	p.Leu309dup	inframe_insertion	11/12	1		ENSP00000379216	P1
MLC1	ENST00000483836.1	n.286_287insGCT		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151914 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000557 AC: 13 AN: 233570 Hom.: 0 AF XY: 0.0000704 AC XY: 9 AN XY: 127780

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000892

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.000129

Gnomad NFE exome AF: 0.0000374

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000310 AC: 45 AN: 1452604 Hom.: 0 Cov.: 39 AF XY: 0.0000374 AC XY: 27 AN XY: 722834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000815

Gnomad4 FIN exome AF: 0.0000435

Gnomad4 NFE exome AF: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152030 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Bravo AF: 0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

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

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs761096481; hg19: chr22-50502592;