rs797044817

Variant names:

• chr19-7529183-CCTT-C
• rs797044817
• NM_020533.3:c.1222_1224delTTC

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. F408F) has been classified as Likely benign.

• 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
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• mucolipidosis type IV

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Myriad Women’s Health, ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Lisch epithelial corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• 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 VariationId is 208022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCOLN1	NM_020533.3	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 10 of 14	ENST00000264079.11	NP_065394.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 10 of 14	1	NM_020533.3	ENSP00000264079.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250738 AF XY: 0.00000737

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60386

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

Oct 12, 2000

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 31, 2019

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Causes mildest MLIV phenotype known -

Sep 25, 2017

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Pathogenic:1

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044817; hg19: chr19-7594069; COSMIC: COSV51182576; COSMIC: COSV51182576;