rs797044817

Variant names:

• chr19-7529183-CCTT-C
• rs797044817
• NM_020533.3:c.1222_1224delTTC

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 13P and 0B. PS3 PM4_Supporting PP5_Very_Strong

The NM_020533.3(MCOLN1):​c.1222_1224delTTC​(p.Phe408del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,460,854 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001363340: "These studies demonstrated that the F408del variant protein showed similar subcellular localization- (Manzoni_2004, Chen_2014) and non-selective cation channel activity to the WT, but demonstrated decreased channel regulation by pH (Raychowdhury_2004) and by phosphoinositide signaling (Chen_2014), as well as a reduced permeability for iron (Dong_2008)."". Synonymous variant affecting the same amino acid position (i.e. F408F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: MCOLN1 NM_020533.3 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:4 O:1
• Conservation: PhyloP100: 7.67
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• mucolipidosis type IV

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Genomics England PanelApp, Ambry Genetics, Myriad Women’s Health, Orphanet, Labcorp Genetics (formerly Invitae)
• Lisch epithelial corneal dystrophy

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001363340: "These studies demonstrated that the F408del variant protein showed similar subcellular localization- (Manzoni_2004, Chen_2014) and non-selective cation channel activity to the WT, but demonstrated decreased channel regulation by pH (Raychowdhury_2004) and by phosphoinositide signaling (Chen_2014), as well as a reduced permeability for iron (Dong_2008)."
• PM4: Nonframeshift variant in NON repetitive region in NM_020533.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 19-7529183-CCTT-C is Pathogenic according to our data. Variant chr19-7529183-CCTT-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208022.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020533.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCOLN1	NM_020533.3	MANE Select	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 10 of 14	NP_065394.1	Q9GZU1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MCOLN1	ENST00000264079.11	TSL:1 MANE Select	c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 10 of 14	ENSP00000264079.5	Q9GZU1
	MCOLN1	ENST00000852002.1		c.1390_1392delTTC	p.Phe464del	conservative_inframe_deletion	Exon 10 of 14	ENSP00000522061.1
	MCOLN1	ENST00000915843.1		c.1222_1224delTTC	p.Phe408del	conservative_inframe_deletion	Exon 10 of 15	ENSP00000585902.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250738 AF XY: 0.00000737

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1460854 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 726814

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52460

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 33

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Mucolipidosis type IV (4)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.7
Mutation Taster		=6/94	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044817; hg19: chr19-7594069; COSMIC: COSV51182576; COSMIC: COSV51182576;