rs80358245

chr22-50080387-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1 PM2 PP3_Moderate PP5_Very_Strong

The NM_015166.4(MLC1):c.278C>T(p.Ser93Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000023 in 1,605,264 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S93S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: 7.19

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 14 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_015166.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933
• PP5: Variant 22-50080387-G-A is Pathogenic according to our data. Variant chr22-50080387-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4714.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-50080387-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.278C>T	p.Ser93Leu	missense_variant	4/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.278C>T	p.Ser93Leu	missense_variant	4/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.278C>T	p.Ser93Leu	missense_variant	4/12	1		P1
MLC1	ENST00000442311.1	c.188C>T	p.Ser63Leu	missense_variant	3/8	5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000171 AC: 4 AN: 234558 Hom.: 0 AF XY: 0.0000237 AC XY: 3 AN XY: 126654

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: 0.00

Gnomad FIN exome AF: 0.0000491

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000241 AC: 35 AN: 1452924 Hom.: 0 Cov.: 33 AF XY: 0.0000277 AC XY: 20 AN XY: 721916

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000229

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000357

Gnomad4 SAS exome AF: 0.0000118

Gnomad4 FIN exome AF: 0.000133

Gnomad4 NFE exome AF: 0.00000722

Gnomad4 OTH exome AF: 0.0000666

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152340 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74506

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

ExAC AF: 0.0000247 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:3 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2003	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 07, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	NM_015166.3(MLC1):c.278C>T(S93L) is classified as likely pathogenic in the context of megalencephalic leukoencephalopathy with subcortical cysts. Sources cited for classification include the following: PMID 14615938, 11254442, 22006981 and 18757878. Classification of NM_015166.3(MLC1):c.278C>T(S93L) is based on the following criteria: This variant has been observed more frequently in patients with clinical diagnoses than in healthy populations and the incidence of disease is extremely low. Please note: this variant was assessed in the context of healthy population screening. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 22, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 12, 2023	This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 93 of the MLC1 protein (p.Ser93Leu). 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 missense change has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 12850517, 14615938, 25796299, 27081509, 27322623). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as c.393C>T. ClinVar contains an entry for this variant (Variation ID: 4714). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MLC1 protein function. Experimental studies have shown that this missense change affects MLC1 function (PMID: 18757878, 22006981). For these reasons, this variant has been classified as Pathogenic. -

Megalencephalic leukoencephalopathy with subcortical cysts Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 24, 2023

Variant summary: MLC1 c.278C>T (p.Ser93Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of four in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.7e-05 in 234558 control chromosomes. c.278C>T has been reported in the literature in multiple individuals affected with Megalencephalic Leukoencephalopathy With Subcortical Cysts 1 (e.g. Shimada_2014). These data indicate that the variant is very likely to be associated with disease. Experimental evidence demonstrated the variant affects protein function (Duarri_2008, Ridder_2014). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
Cadd	Pathogenic	29
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.37	T;T;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.2	M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-4.2	D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0090	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.88
MutPred		0.80		Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP		0.91
MPC		0.77
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.55
gMVP		0.88

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs80358245; hg19: chr22-50518816;