rs1555632971

Variant names:

• chr18-23538609-CC-AT
• rs1555632971
• NM_000271.5:c.2973_2974delGGinsAT

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PP5_Very_Strong

The NM_000271.5(NPC1):​c.2973_2974delGGinsAT​(p.Gly992Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Q991Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NPC1 NM_000271.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 6.09

Genes affected

NPC1 (HGNC:7897): (NPC intracellular cholesterol transporter 1) This gene encodes a large protein that resides in the limiting membrane of endosomes and lysosomes and mediates intracellular cholesterol trafficking via binding of cholesterol to its N-terminal domain. It is predicted to have a cytoplasmic C-terminus, 13 transmembrane domains, and 3 large loops in the lumen of the endosome - the last loop being at the N-terminus. This protein transports low-density lipoproteins to late endosomal/lysosomal compartments where they are hydrolized and released as free cholesterol. Defects in this gene cause Niemann-Pick type C disease, a rare autosomal recessive neurodegenerative disorder characterized by over accumulation of cholesterol and glycosphingolipids in late endosomal/lysosomal compartments.[provided by RefSeq, Aug 2009]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a disulfide_bond (size 55) in uniprot entity NPC1_HUMAN there are 26 pathogenic changes around while only 1 benign (96%) in NM_000271.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 18-23538609-CC-AT is Pathogenic according to our data. Variant chr18-23538609-CC-AT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 539309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPC1	NM_000271.5	c.2973_2974delGGinsAT	p.Gly992Trp	missense_variant		ENST00000269228.10	NP_000262.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPC1	ENST00000269228.10	c.2973_2974delGGinsAT	p.Gly992Trp	missense_variant		1	NM_000271.5	ENSP00000269228.4
NPC1	ENST00000591051.1	c.2049_2050delGGinsAT	p.Gly684Trp	missense_variant		2		ENSP00000467636.1
NPC1	ENST00000591075.1	n.606_607delGGinsAT		non_coding_transcript_exon_variant	Exon 2 of 3	4
NPC1	ENST00000591955.1	n.316_317delGGinsAT		non_coding_transcript_exon_variant	Exon 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

Aug 10, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Niemann-Pick disease, type C1 Pathogenic:1

Jan 11, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NPC1-related disease. A different variant (c.2974G>T) giving rise to the same protein effect observed here (p.Gly992Trp) has been reported to be a very common cause of Niemann-Pick disease type C (PMID: 9634529, 12955717), indicating that this residue may be critical for protein function. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555632971; hg19: chr18-21118573;