ClinVar Miner

Submissions for variant NM_000271.5(NPC1):c.541G>A (p.Ala181Thr)

gnomAD frequency: 0.00011  dbSNP: rs199963560
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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) RCV000594934 SCV000702740 uncertain significance not provided 2017-12-14 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV001248055 SCV001421519 uncertain significance Niemann-Pick disease, type C1 2022-10-02 criteria provided, single submitter clinical testing This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 181 of the NPC1 protein (p.Ala181Thr). This variant is present in population databases (rs199963560, gnomAD 0.06%). 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: 497961). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV001248055 SCV002767724 uncertain significance Niemann-Pick disease, type C1 2024-10-11 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as VOUS – 3B. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0106 - This gene is known to be associated with autosomal recessive disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from alanine to threonine. (N) 0251 - Variant is heterozygous. (N) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (34 Heterozygotes, 0 Homozygotes). (P) 0502 - Missense variant with conflicting in-silico predictions and/or uninformative conservation. (N) 0601 - Variant affects at least one well-established (essential) functional domain or motif, NPC1 N terminal subdomain. (Kwon, H. et al. (2009)). (P) 0705 - No comparable variants have previous evidence for pathogenicity. (N) 0804 - Variant has previously been described as variant of uncertain significance in multiple independent cases. (LOVD, ClinVar, Zech, M. et al. (2013)). (N) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Fulgent Genetics, Fulgent Genetics RCV001248055 SCV002783825 uncertain significance Niemann-Pick disease, type C1 2022-02-23 criteria provided, single submitter clinical testing
Ambry Genetics RCV002531010 SCV003545510 uncertain significance Inborn genetic diseases 2022-02-10 criteria provided, single submitter clinical testing The c.541G>A (p.A181T) alteration is located in exon 5 (coding exon 5) of the NPC1 gene. This alteration results from a G to A substitution at nucleotide position 541, causing the alanine (A) at amino acid position 181 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV000594934 SCV005401522 uncertain significance not provided 2024-05-18 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported heterozygous in individuals with early-onset Parkinson disease in published literature; however, further clinical information was not provided (PMID: 35861376); This variant is associated with the following publications: (PMID: 35861376, 24386122)
Natera, Inc. RCV001248055 SCV002095228 uncertain significance Niemann-Pick disease, type C1 2020-01-29 no assertion criteria provided clinical testing

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