19-7529689-G-T

Position:

chr19-7529689-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_020533.3(MCOLN1):c.1336G>T(p.Val446Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,838 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V446M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MCOLN1
NM_020533.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 9.60

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:

MCOLN1 (HGNC:):

MCOLN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-7529689-G-A is described in Lovd as [Likely_pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 19-7529689-G-T is Pathogenic according to our data. Variant chr19-7529689-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 208033.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MCOLN1	NM_020533.3 linkuse as main transcript	c.1336G>T	p.Val446Leu	missense_variant	11/14	ENST00000264079.11	NP_065394.1	Q9GZU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11 linkuse as main transcript	c.1336G>T	p.Val446Leu	missense_variant	11/14	1	NM_020533.3	ENSP00000264079.5		Q9GZU1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251458

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.00000342

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

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:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Mucolipidosis type IV

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2023	ClinVar contains an entry for this variant (Variation ID: 208033). 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: 14749347, 18794901, 25119295, 27670435). 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. This missense change has been observed in individual(s) with mucolipidosis type IV (PMID: 11030752). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 446 of the MCOLN1 protein (p.Val446Leu). This variant is present in population databases (no rsID available, gnomAD 0.01%). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 25, 2024	Variant summary: MCOLN1 c.1336G>T (p.Val446Leu) results in a conservative amino acid change located in the polycystin cation channel, PKD1/PKD2 domain (IPR013122) of the encoded protein sequence. Three 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 251458 control chromosomes (gnomAD). c.1336G>T has been reported in the literature in at least one homozygous individual from a consanguineous family affected with Mucolipidosis Type 4 (Sun_2000). These data indicate that the variant may be associated with disease. Several publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in resistance to the inhibition of ion channel activity at low pH (Roychowdhury_2004), significantly reduced co-localization to lysosomes (Chen_2014), and impaired cationic iron permeability resulting in <10% of normal activity (Dong_2008). The following publications have been ascertained in the context of this evaluation (PMID: 11030752, 18794901, 14749347, 25119295). ClinVar contains an entry for this variant (Variation ID: 208033). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.1336G>T (p.V446L) alteration is located in coding exon 11 of the MCOLN1 gene. This alteration results from a G to T substitution at nucleotide position 1336, causing the valine (V) at amino acid position 446 to be replaced by a leucine (L). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.1336G>T alteration was observed in 0.0016% (4/251458) of total alleles studied, with a frequency of 0.012% (4/34592) in the Latino subpopulation. The amino acid change has been observed in affected individuals: _x000D_ _x000D_ This alteration has been observed homozygous in a patient with a severe presentation of mucolipidosis IV (Sun, 2000; Wakabayashi, 2011; Yamaguchi, 2019). Functional analysis reveals there may be a damaging effect of the amino acid alteration: _x000D_ _x000D_ Several studies have demonstrated using functional data that the p.V446L alteration can interfere with correct subcellular localization (Dong, 2008; Chen, 2014; Pryor, 2006). Other studies suggest the alteration impairs channel function (Dong, 2008), but this was not consistently observed (Raychowdhury, 2004). Based on the available evidence, this alteration is classified as likely pathogenic. -

Mucolipidosis type IV;C2749050:Lisch epithelial corneal dystrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 30, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.17

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.062

MetaRNN

Pathogenic

0.98

MetaSVM

Benign

-0.29

MutationAssessor

Uncertain

2.7

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.49

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.0070

Polyphen

0.93

Vest4

0.93

MutPred

0.93

Gain of sheet (P = 0.1945);

MVP

0.81

MPC

2.3

ClinPred

0.88

GERP RS

5.5

Varity_R

0.83

gMVP

0.85

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

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