ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.3548G>A (p.Arg1183His)

gnomAD frequency: 0.00047  dbSNP: rs148035987
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000729875 SCV000857568 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing
Invitae RCV000793551 SCV000932909 uncertain significance Niemann-Pick disease, type C1 2022-10-25 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1183 of the NPC1 protein (p.Arg1183His). This variant is present in population databases (rs148035987, gnomAD 0.2%). This variant has not been reported in the literature in individuals affected with NPC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 594562). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NPC1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Illumina Laboratory Services, Illumina RCV000793551 SCV001282154 uncertain significance Niemann-Pick disease, type C1 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
GeneDx RCV000729875 SCV002015739 uncertain significance not provided 2021-11-08 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: Kandakatla2014[Article])
Fulgent Genetics, Fulgent Genetics RCV000793551 SCV002780385 uncertain significance Niemann-Pick disease, type C1 2021-12-13 criteria provided, single submitter clinical testing
PreventionGenetics, part of Exact Sciences RCV003908034 SCV004727436 likely benign NPC1-related disorder 2022-02-28 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Natera, Inc. RCV000793551 SCV001453828 uncertain significance Niemann-Pick disease, type C1 2020-09-16 no assertion criteria provided clinical testing

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