ClinVar Genomic variation as it relates to human health

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). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.

Variant summary: NPC2 c.441+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Two of two in-silico tools predict a benign effect of the variant on protein function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. In one study, analysis of the variant using independent cell lines revealed multiple splicing events, the most prominent of which resulted in the insertion of 16 bases, leading to the alteration of the terminal 4 amino acids and the addition of 86 additional amino acids to the protein (Wassif_2016). In a different study, RT-PCR analysis showed the variant resulted in the synthesis of three aberrant transcripts, two of which would lead to a shift in the reading frame and premature termination codon (Cupidi_2016). Despite the impact on splicing, it is unclear what impact this would have on protein function. The variant allele was found at a frequency of 0.0037 in 254898 control chromosomes, predominantly at a frequency of 0.0064 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9.45 fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC2 causing Niemann-Pick Disease Type C phenotype (0.00068), suggesting that the variant is a benign polymorphism. c.441+1G>A has been reported in the literature in patients with various neurological and psychiatric symptoms, with liver storage disease and in patients with not fully described phenotypes, and in cases where the second allele was not found/reported (Bauer_2013, Fernandez-Marmiesse_2014, McKay_2014, Wassif_2016, Zech_2013, Cupidi_2016). The variant was also reported in individuals affected with Niemann-Pick Disease Type C in the homozygous state, including a family with two fetuses with cystic hygroma (Gheldof_2018, Ples_2018, Reunert_2016). These data do not provide unequivocal evidence for pathogenicity. Ten clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Five submitters classified the variant as benign/likely benign while five classified the variant as VUS. Based on the evidence outlined above, the variant was classified as uncertain significance.

Converted during submission to Uncertain significance.

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PVS1,PP5.

NM_006432.3(NPC2):c.441+1G>A is a canonical splice variant classified as a variant of uncertain significance in the context of Niemann-Pick disease type C2. c.441+1G>A has been observed in cases with relevant disease (PMID: 26981555, 30548430, Mikhaylova_2011_(no PMID; abstract)). Functional assessments of this variant are available in the literature (PMID: 25764212, 27792009). c.441+1G>A has been observed in population frequency databases (gnomAD: NFE 0.63%). In summary, there is insufficient evidence to classify NM_006432.3(NPC2):c.441+1G>A as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.

BA1, PVS1_moderate

This variant is associated with the following publications: (PMID: 24386122, 27792009, 23352160, 23773996, 25764212, 24767253, 29431110, 30548430, 29928259)

NPC2: BS2

The NPC2 c.441+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant was detected in the heterozygous state in one patient with a possible Niemann-Pick disease Type C phenotype and with no other pathogenic or likely pathogenic variants (Bauer et al. 2013. PubMed ID: 23773996). Another study reported this variant in the heterozygous state in patients with two autosomal dominant disorders (Parkinson's disease and frontotemporal lobar degeneration), and also in one control individual (Zech et al. 2013. PubMed ID: 24386122). At PreventionGenetics, we previously detected this variant in the heterozygous state in several other patients with various Niemann-Pick phenotypes. However, this variant is reported in 0.65% of alleles in individuals of European (Non-Finnish) descent in gnomAD, including three homozygotes, which might be too common to be a highly penetrant cause of disease. While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.