chr19-7528638-CT-C

Variant names:

• chr19-7528638-CT-C
• rs755042147
• NM_020533.3:c.920delT

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.920delT​(p.Leu307ProfsTer65) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000118 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: MCOLN1 NM_020533.3 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 3.76

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]

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 19-7528638-CT-C is Pathogenic according to our data. Variant chr19-7528638-CT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-7528638-CT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MCOLN1	NM_020533.3	c.920delT	p.Leu307ProfsTer65	frameshift_variant	Exon 8 of 14	ENST00000264079.11	NP_065394.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MCOLN1	ENST00000264079.11	c.920delT	p.Leu307ProfsTer65	frameshift_variant	Exon 8 of 14	1	NM_020533.3	ENSP00000264079.5
MCOLN1	ENST00000394321.9	n.1235delT		non_coding_transcript_exon_variant	Exon 7 of 13	2
MCOLN1	ENST00000595860.5	n.-15delT		upstream_gene_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251390 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135882

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1461874 Hom.: 0 Cov.: 33 AF XY: 0.00000550 AC XY: 4 AN XY: 727240

Gnomad4 AFR exome AF: 0.00

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: 0.0000135

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74378

Gnomad4 AFR AF: 0.00

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: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucolipidosis type IV Pathogenic:4

Jul 30, 2020

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.920delT (p.Leu307ProfsX65) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 251390 control chromosomes (gnomAD). c.920delT has been reported in the literature in one individual affected with Mucolipidosis Type 4 (Goldin_2008). These data indicate that the variant may be associated with disease. Three ClinVar submitters (evaluation after 2014) cite the variant as pathogenic (2x) and likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as pathogenic. -

Nov 29, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 12, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Leu307Profs*65) 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 present in population databases (rs755042147, gnomAD 0.002%). This premature translational stop signal has been observed in individual(s) with mucolipidosis type IV (PMID: 18326692). ClinVar contains an entry for this variant (Variation ID: 208039). 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. -

Inborn genetic diseases Pathogenic:1

Dec 04, 2023

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.920delT (p.L307Pfs*65) alteration, located in exon 8 (coding exon 8) of the MCOLN1 gene, consists of a deletion of one nucleotide at position 920, causing a translational frameshift with a predicted alternate stop codon after 65 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. Based on data from gnomAD, the c.920delT allele has an overall frequency of 0.001% (4/282790) total alleles studied. The highest observed frequency was 0.003% (4/129108) of European (non-Finnish) alleles. This variant has been reported compound heterozygous in one individual with features consistent with Mucolipidosis IV (Goldin, 2008). Based on the available evidence, this alteration is classified as pathogenic. -

Mucolipidosis type IV;C2749050:Lisch epithelial corneal dystrophy Pathogenic:1

Apr 08, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs755042147; hg19: chr19-7593524;