Variant rs121908371 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_020533.3(MCOLN1):c.964C>T(p.Arg322*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,614,094 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 (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MCOLN1
NM_020533.3 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 0.374

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 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 19-7528683-C-T is Pathogenic according to our data. Variant chr19-7528683-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 5133.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 link	c.964C>T	p.Arg322*	stop_gained	8/14	ENST00000264079.11	NP_065394.1	Q9GZU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MCOLN1	ENST00000264079.11 link	c.964C>T	p.Arg322*	stop_gained	8/14	1	NM_020533.3	ENSP00000264079.5	Q9GZU1
MCOLN1	ENST00000394321.9 link	n.1279C>T		non_coding_transcript_exon_variant	7/13	2
MCOLN1	ENST00000595860.5 link	n.30C>T		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152234

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74362

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:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucolipidosis type IV

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2023	This sequence change creates a premature translational stop signal (p.Arg322*) in the MCOLN1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MCOLN1 are known to be pathogenic (PMID: 11030752, 11317355, 37972748). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individuals with mucolipidosis type IV (PMID: 10973263, 11317355). ClinVar contains an entry for this variant (Variation ID: 5133). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 24, 2019	Variant summary: MCOLN1 c.964C>T (p.Arg322X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 251318 control chromosomes (gnomAD). c.964C>T has been reported in the literature in homozygous and compound heterozygous individuals affected with Mucolipidosis Type 4 (Bargal_2000, Bargal_2001). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 02, 2022

The c.964C>T (p.R322*) alteration, located in exon 8 (coding exon 8) of the MCOLN1 gene, consists of a C to T substitution at nucleotide position 964. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 322. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This alteration has been reported in the homozygous and compound heterozygous states in individuals with mucolipidosis IV (Bargal, 2000; Bargal, 2001; Ziats, 2020). Based on the available evidence, this alteration is classified as pathogenic. -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 25, 2024

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 12125810, 37972748, 21763169, 10973263, 31618753, 20852892, 35425852, 11317355) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.56

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.54

Vest4

0.84

GERP RS

5.3

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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