rs1057517090

Positions:

• chr22-50077470-CAGCAGGA-C

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.449_455del​(p.Leu150ArgfsTer9) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,458 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: 0.0000014 (0 hom.)
• Consequence: MLC1 NM_015166.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4 U:1
• Conservation: PhyloP100: 7.75

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 22-50077470-CAGCAGGA-C is Pathogenic according to our data. Variant chr22-50077470-CAGCAGGA-C is described in ClinVar as [Pathogenic]. Clinvar id is 371207.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.449_455del	p.Leu150ArgfsTer9	frameshift_variant	6/12	ENST00000311597.10	NP_055981.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLC1	ENST00000311597.10	c.449_455del	p.Leu150ArgfsTer9	frameshift_variant	6/12	1	NM_015166.4	ENSP00000310375	P1
MLC1	ENST00000395876.6	c.449_455del	p.Leu150ArgfsTer9	frameshift_variant	6/12	1		ENSP00000379216	P1
MLC1	ENST00000442311.1	c.359_365del	p.Leu120ArgfsTer9	frameshift_variant	5/8	5		ENSP00000401385

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461458 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 727050

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2001	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 11, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jul 27, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Myelin Disorders Clinic-Children's Medical Center/Medical Genetics Lab-Tarbiat Modares University, Children's Medical Center, Pediatrics Center of Excellence,	-	- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 28, 2023

ClinVar contains an entry for this variant (Variation ID: 371207). For these reasons, this variant has been classified as Pathogenic. This variant is also known as 564-570del (L149 frameshift). This premature translational stop signal has been observed in individual(s) with megalencephalic leukoencephalopathy with subcortical cysts (PMID: 11254442). This variant is present in population databases (no rsID available, gnomAD 0.007%). This sequence change creates a premature translational stop signal (p.Leu150Argfs*9) 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). -

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: rs1057517090; hg19: chr22-50515899;