rs104886461

Variant names:

Variant summary

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

The NM_020533.3(MCOLN1):c.406-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000105 in 1,613,752 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

MCOLN1
NM_020533.3 splice_acceptor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:12O:2

Conservation

PhyloP100: 6.13

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

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-7526759-A-G is Pathogenic according to our data. Variant chr19-7526759-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 5131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7526759-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCOLN1	NM_020533.3 link	c.406-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 13	ENST00000264079.11	NP_065394.1	Q9GZU1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11 link	c.406-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 13	1	NM_020533.3	ENSP00000264079.5		Q9GZU1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00317

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:

0.000207

AC:

AN:

251204

Hom.:

AF XY:

0.000206

AC XY:

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00417

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000616

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

157

AN:

1461560

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

727084

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.00390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00317

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:

0.000391

Hom.:

Bravo

AF:

0.000136

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12Other:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mucolipidosis type IV

Pathogenic:7Other:1

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 20, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Oct 18, 2019	NM_020533.2(MCOLN1):c.406-2A>G(aka IVS3-2A>G) is classified as pathogenic in the context of mucolipidosis IV. Sources cited for classification include the following: PMID 11317355, 11030752, 11013137, 10973263, 16645217, 16287144, 11845410, 17384215, 1471493347. Classification of NM_020533.2(MCOLN1):c.406-2A>G(aka IVS3-2A>G) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. -
not provided, no classification provided	literature only	GeneReviews	-	Accounts for 77% of pathogenic variants in Ashkenazi Jewish persons. Approximately 60% of individuals with MLIV of Ashkenazi Jewish heritage in the US are homozygotes for the c.406-2A>G intronic acceptor splice site pathogenic variant. An estimated 33% are compound heterozygotes for this variant and the 6.4-kb deletion. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 23, 2025	This sequence change affects an acceptor splice site in intron 3 of the MCOLN1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or altered protein product. This variant is present in population databases (rs104886461, gnomAD 0.4%). Disruption of this splice site has been observed in individuals with Lisch epithelial corneal dystrophy and/or mucolipidosis type IV (PMID: 11013137, 19815695, 37972748). It is commonly reported in individuals of Ashkenazi ancestry (PMID: 11013137, 19815695). ClinVar contains an entry for this variant (Variation ID: 5131). Studies have shown that disruption of this splice site results in exon 4 skipping, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11013137). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Sep 24, 2018	The MCOLN1 c.406-2A>G variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. Across a selection of the available literature, the c.406-2A>G variant has been identified in a homozygous state in 13 probands and six in a compound heterozygous state including one sibling pair with mucolipidosis (Bargal et al. 2000; Bassi et al. 2000). The variant has also been found in unaffected heterozygous carriers. The c.406-2A>G variant is reported at a frequency of 0.004237 in the Ashkenazi Jewish population of the Genome Aggregation Database. The c.406-2A>G variant causes exon skipping which results in a protein predicted to retain only 3.6% of wild type protein (Bassi et al. 2000). Based on the evidence, the c.406-2A>G variant is classified as pathogenic for mucolipidosis, type IV. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 2001	- -

not provided

Pathogenic:3Other:1

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 03, 2024	Reverse transcription polymerase chain reaction of RNA extracted from individuals affected with mucolipidosis type IV who harbored c.406-2 A>G revealed aberrant spicing (PMID: 10973263); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 21228398, 11845410, 31663226, 10973263, 28392473, 10441585, 19815695, 11013137, 11030752, 11317355, 23891399, 30609409, 31980526, 37972748, 37267771, 35425852, 17384215, 23555759, 16645217, 16287144, 11551108, 15523648) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 08, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	MCOLN1: PM3:Very Strong, PVS1, PM2 -
not provided, no classification provided	literature only	SNPedia	-	- -

Mucolipidosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 10, 2017

The c.406-2A>G variant (NM_020433.2) in MCOLN1 has been reported in at least 12 homozygous and 1 compound heterozygous individuals with mucolipidosis type IV (B argal 2000). This variant has also been reported in ClinVar (Variation ID#5131), as pathogenic by multiple laboratories. This variant occurs in the invariant re gion (+/- 1,2) of the splice consensus sequence and has been demonstrated to imp act splicing and lead to skipping of exon 4, introducing a frameshift (Bargal 20 00, Edelmann 2002). This variant has been identified in 0.42% (43/10148) of Ash kenazi Jewish chromosomes by the Genome Aggregation Database (gnomAD, http://gno mad.broadinstitute.org; dbSNP rs104886461) and has been reported as a founder mu tation in the Ashkenazi Jewish population (Edelmann 2002, Hantash 2006) . Bialle lic loss of function of the MCOLN1 gene is an established disease mechanism for mucolipidosis type IV. In summary, this variant meets criteria to be classified as pathogenic for mucolipidosis type IV in an autosomal recessive manner based u pon its biallelic occurrence in individuals with this disease and functional imp act on the protein. ACMG/AMP Criteria applied: PVS1, PM3_Strong (upgraded to str ong based on multiple occurrences), PP5. -

Mucolipidosis type IV;C2749050:Lisch epithelial corneal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.86

FATHMM_MKL

Uncertain

0.95

GERP RS

5.2

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.91

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_AL_spliceai

1.0

Position offset: 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