rs797044817

Positions:

• chr19-7529183-CCTT-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PM4_Supporting PP5_Very_Strong

The NM_020533.3(MCOLN1):​c.1222_1224delTTC​(p.Phe408del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MCOLN1 NM_020533.3 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.67

Genes affected

MCOLN1 (HGNC:13356): (mucolipin TRP cation channel 1) This gene encodes a memberof the transient receptor potential (TRP) cation channel gene family. The transmembrane protein localizes to intracellular vesicular membranes including lysosomes, and functions in the late endocytic pathway and in the regulation of lysosomal exocytosis. The channel is permeable to Ca(2+), Fe(2+), Na(+), K(+), and H(+), and is modulated by changes in Ca(2+) concentration. Mutations in this gene result in mucolipidosis type IV. [provided by RefSeq, Oct 2009]

MCOLN1 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_020533.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-7529183-CCTT-C is Pathogenic according to our data. Variant chr19-7529183-CCTT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208022.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
MCOLN1	NM_020533.3	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	10/14	ENST00000264079.11	NP_065394.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	10/14	1	NM_020533.3	ENSP00000264079.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250738 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135614

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: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460854 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726814

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucolipidosis type IV Pathogenic:3 Other:1

not provided, no classification provided	literature only	GeneReviews	-	Causes mildest MLIV phenotype known -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 12, 2000	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 31, 2019	Variant summary: MCOLN1 c.1222_1224delTTC (p.Phe408del) results in an in-frame deletion that is predicted to remove one amino acid from the encoded protein. The variant allele was found at a frequency of 4e-06 in 250738 control chromosomes (gnomAD). c.1222_1224delTTC has been reported in the literature in a compound heterozygous individual affected with a mild form of Mucolipidosis Type 4 (Sun_2000, Bargal_2001, Altarescu_2002). These data indicate that the variant may be associated with disease. Several publications reported experimental evidence evaluating an impact on protein function. These studies demonstrated that the F408del variant protein showed similar subcellular localization- (Manzoni_2004, Chen_2014) and non-selective cation channel activity to the WT, but demonstrated decreased channel regulation by pH (Raychowdhury_2004) and by phosphoinositide signaling (Chen_2014), as well as a reduced permeability for iron (Dong_2008). The largely preserved channel activity with a partial defect in regulation has been proposed as an explanation for the milder reported disease phenotype. One ClinVar submission (evaluation after 2014) cited the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic for an attenuated disease phenotype. -
Likely pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 25, 2017	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2024

MCOLN1: PM2, PM3, PM4:Supporting, PS3:Supporting -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs797044817; hg19: chr19-7594069;