rs281875310

chr22-50083111-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_015166.4(MLC1):c.240G>A(p.Met80Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000186 in 1,614,006 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: MLC1 NM_015166.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 O:1
• Conservation: PhyloP100: 7.21

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_015166.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.981
• PP5: Variant 22-50083111-C-T is Pathogenic according to our data. Variant chr22-50083111-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 68790.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=2, not_provided=1}. Variant chr22-50083111-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLC1	NM_015166.4	c.240G>A	p.Met80Ile	missense_variant	3/12	ENST00000311597.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLC1	ENST00000311597.10	c.240G>A	p.Met80Ile	missense_variant	3/12	1	NM_015166.4	P1
MLC1	ENST00000395876.6	c.240G>A	p.Met80Ile	missense_variant	3/12	1		P1
MLC1	ENST00000442311.1	c.177+1615G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251256 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135840

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727218

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152158 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74316

Gnomad4 AFR AF: 0.0000483

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: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Megalencephalic leukoencephalopathy with subcortical cysts 1 Pathogenic:2 Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A homozygous missense variant was identified, NM_015166.3(MLC1):c.240G>A in exon 3 of 12 of the MLC1 gene. This substitution is predicted to create a minor amino acid change from a methionine to an isoleucine at position 80 of the protein, NP_055981.1(MLC1):p.(Met80Ile). The methionine at this position has very high conservation (100 vertebrates, UCSC), but is not situated in a known functional domain. In silico software predicts this variant to be damaging (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0004% (1 heterozygote, 0 homozygotes). The variant has previously been reported in two patients with megalencephalic leukoencephalopathy with subcortical cysts (ClinVar, Ilja Boor, P., et al . (2006)). A different variant in the same codon resulting in a change to a valine, p.(Met80Val), has also been reported in a patient with the same condition (Montagna, G. et al . (2006). Based on information available at the time of curation, this variant has been classified as LIKELY PATHOGENIC. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Jul 04, 2022	ACMG classification criteria: PS4 supporting, PM2 moderated, PM3 strong, PP3 supporting -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 08, 2021	NM_015166.3(MLC1):c.240G>A(M80I) is a missense variant classified as a variant of uncertain significance in the context of megalencephalic leukoencephalopathy with subcortical cysts. M80I has been observed in cases with relevant disease (PMID: 16652334). Functional assessments of this variant are not available in the literature. M80I has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, there is insufficient evidence to classify NM_015166.3(MLC1):c.240G>A(M80I) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 25, 2022	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 80 of the MLC1 protein (p.Met80Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of megalencephalic leukoencephalopathy with subcortical cysts (PMID: 16652334; Invitae). ClinVar contains an entry for this variant (Variation ID: 68790). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This variant disrupts the p.Met80 amino acid residue in MLC1. Other variant(s) that disrupt this residue have been observed in individuals with MLC1-related conditions (PMID: 16470554), which suggests that this may be a clinically significant amino acid residue. 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. -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

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	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.3	M;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.2	D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.91	P;P
Vest4		0.96
MutPred		0.93		Loss of catalytic residue at V75 (P = 0.4162);Loss of catalytic residue at V75 (P = 0.4162);
MVP		0.85
MPC		0.90
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.83
gMVP		0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs281875310; hg19: chr22-50521540;