rs758902805
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000271.5(NPC1):c.3614C>G(p.Thr1205Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1205K) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000271.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NPC1 | NM_000271.5 | c.3614C>G | p.Thr1205Arg | missense_variant | 24/25 | ENST00000269228.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NPC1 | ENST00000269228.10 | c.3614C>G | p.Thr1205Arg | missense_variant | 24/25 | 1 | NM_000271.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461838Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2AN XY: 727222
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Niemann-Pick disease, type C Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | May 10, 2016 | The p.Thr1205Arg variant in NPC1 has been previously reported in three individua ls with Niemann-Pick disease type C (Yamamoto 2000, Park 2003, Jahnova 2014). At least 2 of these individuals carried the variant in a compound heterozygous sta te (Yamamoto 2000, Jahnova 2014). This variant was absent from large population studies. Computational prediction tools and conservation analysis suggest that t he p.Thr1205Arg variant may impact the protein, though this information is not p redictive enough to determine pathogenicity. In summary, although additional stu dies are required to fully establish its clinical significance, the p.Thr1205Arg variant is likely pathogenic. - |
Niemann-Pick disease, type C1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2018 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Thr1205 amino acid residue in NPC1. Other variant(s) that disrupt this residue have been observed in affected individuals (PMID: 15130691, 22676771, 12955717, 23430855, 11182931, 25236789), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed in several individuals affected with Niemann-Pick Type C (PMID: 11182931, 22676771, 25236789). ClinVar contains an entry for this variant (Variation ID: 505018). This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with arginine at codon 1205 of the NPC1 protein (p.Thr1205Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at