rs767122713

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_020533.3(MCOLN1):c.694A>C(p.Thr232Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,613,794 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 (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

MCOLN1
NM_020533.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5O:1

Conservation

PhyloP100: 4.89

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

PP5

Variant 19-7527877-A-C is Pathogenic according to our data. Variant chr19-7527877-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208021.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 link	c.694A>C	p.Thr232Pro	missense_variant	Exon 6 of 14	ENST00000264079.11	NP_065394.1	Q9GZU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MCOLN1	ENST00000264079.11 link	c.694A>C	p.Thr232Pro	missense_variant	Exon 6 of 14	1	NM_020533.3	ENSP00000264079.5	Q9GZU1
MCOLN1	ENST00000601003.1 link	c.585A>C	p.Ser195Ser	synonymous_variant	Exon 5 of 5	3		ENSP00000469074.1	M0QXD0
MCOLN1	ENST00000394321.9 link	n.1009A>C		non_coding_transcript_exon_variant	Exon 5 of 13	2
MCOLN1	ENST00000598406.1 link	n.*106A>C		downstream_gene_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

show subpopulations

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:

0.0000159

AC:

AN:

251404

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135888

show subpopulations

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1461714

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

727184

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

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:

0.0000648

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152080

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74288

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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

Alfa

AF:

0.0000333

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucolipidosis type IV

Pathogenic:4Other:1

Jun 14, 2019

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: MCOLN1 c.694A>C (p.Thr232Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251404 control chromosomes (gnomAD). The variant, c.694A>C, has been reported in the literature in individuals affected with Mucolipidosis Type 4 (Bargal_2001, Slaugenhaupt_2002, Geer_2010, Chaer_2018). These data indicate that the variant may be associated with disease. One publication, Dong_2008, reports this variant are shown to impair TRPML1s ability to permeate Fe2+ and residual activity is <10% of normal. One submitter has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

Associated with severe phenotype -

Baylor Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 232 of the MCOLN1 protein (p.Thr232Pro). This variant is present in population databases (rs767122713, gnomAD 0.004%). This missense change has been observed in individual(s) with mucolipidosis type IV (PMID: 11317355, 20159435, 30120981). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 208021). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on MCOLN1 protein function. Experimental studies have shown that this missense change affects MCOLN1 function (PMID: 15178326, 18794901, 28112729). For these reasons, this variant has been classified as Pathogenic. -

Mucolipidosis type IV;C2749050:Lisch epithelial corneal dystrophy

Pathogenic:1

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.70

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

M_CAP

Benign

0.073

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.14

MutationAssessor

Uncertain

2.5

PrimateAI

Benign

0.44

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.74

Sift

Benign

0.049

Sift4G

Benign

0.19

Polyphen

0.99

Vest4

0.90

MVP

0.85

MPC

1.3

ClinPred

0.85

GERP RS

5.2

Varity_R

0.92

gMVP

0.95

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over