rs80358242

Positions:

• chr22-50084727-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_015166.4(MLC1):​c.176G>A​(p.Gly59Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,461,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense, splice_region
• Scores: Splicing: ADA: 0.9637
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8 O:1
• Conservation: PhyloP100: 6.89

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]

MLC1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 22-50084727-C-T is Pathogenic according to our data. Variant chr22-50084727-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50084727-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLC1	NM_015166.4	c.176G>A	p.Gly59Glu	missense_variant, splice_region_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.176G>A	p.Gly59Glu	missense_variant, splice_region_variant	2/12	1	NM_015166.4	ENSP00000310375.6
MLC1	ENST00000395876.6	c.176G>A	p.Gly59Glu	missense_variant, splice_region_variant	2/12	1		ENSP00000379216.2
MLC1	ENST00000442311.1	c.176G>A	p.Gly59Glu	missense_variant, splice_region_variant	2/8	5		ENSP00000401385.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461604 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727106

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:4 Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	NM_015166.3(MLC1):c.176G>A(G59E) is classified as likely pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 12189496, 23793458 and 18757878. Classification of NM_015166.3(MLC1):c.176G>A(G59E) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and there is functional data showing deficient protein function. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 01, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 01, 2002	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Dec 14, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2024	Published functional studies demonstrate reduced expression of the protein at the plasma membrane and reduced protein stability (PMID: 18757878); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23793458, 22975760, 18757878, 12189496) -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 16, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 59 of the MLC1 protein (p.Gly59Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with megalencephalic leukoencephalopathy (PMID: 12189496). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 4721). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 23793458). For these reasons, this variant has been classified as Pathogenic. -

Megalencephalic leukoencephalopathy with subcortical cysts Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 12, 2022	Variant summary: MLC1 c.176G>A (p.Gly59Glu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 249342 control chromosomes. c.176G>A has been reported in the literature to segregate with disease in multiple homozygous individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (Ben-Zeev_2002). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, demonstrating reduced expression of the protein in the plasma membrane and reduced protein stability (Duarri_2008). Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic (n=3) and likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 28, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.89	.;D;T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.3	M;M;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-7.6	D;D;D
REVEL	Pathogenic	0.89
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	D;D;.
Vest4		1.0
MutPred		0.97		Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP		0.94
MPC		0.90
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.0		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: rs80358242; hg19: chr22-50523156;