22-50084767-AG-AGG

Position:

• chr22-50084767-AG-AGG

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015166.4(MLC1):​c.135_136insC​(p.Cys46LeufsTer34) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: MLC1 NM_015166.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: -2.59

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-50084767-A-AG is Pathogenic according to our data. Variant chr22-50084767-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 4722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.135_136insC	p.Cys46LeufsTer34	frameshift_variant	2/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.135_136insC	p.Cys46LeufsTer34	frameshift_variant	2/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.135_136insC	p.Cys46LeufsTer34	frameshift_variant	2/12	1		ENSP00000379216	P1
MLC1	ENST00000442311.1	c.135_136insC	p.Cys46LeufsTer105	frameshift_variant	2/8	5		ENSP00000401385

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000280 AC: 7 AN: 250390 Hom.: 0 AF XY: 0.0000517 AC XY: 7 AN XY: 135472

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461758 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Frameshift variant c.135dupC in Exon 2 of the MLC1 gene that results in the amino acid substitution p.Cys46fs*34 was identified. The observed variant has a minor allele frequency of 0.00003% in gnomAD exomes and and novel in 1KG, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease- causing. ClinVar has also classified this variant as Pathogenic [Variation ID: 4722]. The observed variation has been previously reported in individuals with megalencephalic leukoencephalopathy (Shukla P, et.al., 2011). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 13, 2019	NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is classified as pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 15037685, 14572144, 22006981, 12189496 and 11935341. Classification of NM_015166.3(MLC1):c.135dupC(aka C46Lfs*34) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 17, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 17, 2024	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	This sequence change creates a premature translational stop signal (p.Cys46Leufs*34) 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). This variant is present in population databases (rs80358241, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with megalencephalic leukoencephalopathy (PMID: 11935341, 12189496, 21555057). ClinVar contains an entry for this variant (Variation ID: 4722). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2018	The c.135dupC variant in the MLC1 gene has been reported in the homozygous state in several unrelated patients with MLC (Leegwater et al., 2002; Ben-Zeev et al., 2002; Ridder et al., 2011; Saini et al., 2015). The c.135dupC variant causes a frameshift starting with codon Cysteine 46, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 34 of the new reading frame, denoted p.Cys46LeufsX34. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.135dupC variant is observed in 7/245210 (0.003%) alleles in large population cohorts We interpret c.135dupC as a pathogenic variant. -

Megalencephalic leukoencephalopathy with subcortical cysts Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs80358241; hg19: chr22-50523196;