rs1057516904

Positions:

• chr19-7528881-G-GA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_020533.3(MCOLN1):​c.1047dupA​(p.Phe350fs) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: MCOLN1 NM_020533.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 7.01

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 (HGNC:):

ACMG classification

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 19-7528881-G-GA is Pathogenic according to our data. Variant chr19-7528881-G-GA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 370970.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	c.1047dupA	p.Phe350fs	frameshift_variant	9/14	ENST00000264079.11	NP_065394.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11	c.1047dupA	p.Phe350fs	frameshift_variant	9/14	1	NM_020533.3	ENSP00000264079.5
MCOLN1	ENST00000394321.9	n.1362dupA		non_coding_transcript_exon_variant	8/13	2
MCOLN1	ENST00000595860.5	n.230dupA		non_coding_transcript_exon_variant	1/4	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucolipidosis type IV Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	May 24, 2016	- -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 31, 2016

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Aug 21, 2018

The c.1047dupA variant in the MCOLN1 gene has not been reported previously as a pathogenicvariant nor as a benign variant, to our knowledge. The c.1047dupA variant has been reported as likelypathogenic in ClinVar by a different clinical laboratory, but additional evidence is not available(ClinVar SCV000486412.1; Landrum et al., 2016). The c.1047dupA variant causes a frameshiftstarting with codon Phenylalanine 350, changes this amino acid to an Isoleucine residue, and creates apremature Stop codon at position 113 of the new reading frame, denoted p.Phe350IlefsX113. Thisvariant is predicted to cause loss of normal protein function either through protein truncation ornonsense-mediated mRNA decay. The c.1047dupA variant is not observed in large population cohorts(Lek et al., 2016). We interpret c.1047dupA as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs1057516904; hg19: chr19-7593767;