Submissions for variant NM_006432.5(NPC2):c.88G>A (p.Val30Met)

gnomAD frequency: 0.00122  dbSNP: rs151220873

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000362578	SCV000331094	benign	not specified	2015-08-25	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080727	SCV001013996	benign	Niemann-Pick disease, type C2	2025-01-27	criteria provided, single submitter	clinical testing
Mendelics	RCV000675984	SCV001135068	likely benign	not provided	2019-05-28	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001080727	SCV001716365	benign	Niemann-Pick disease, type C2	2021-05-18	criteria provided, single submitter	clinical testing
GeneDx	RCV000675984	SCV001782622	likely benign	not provided	2020-10-06	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 32858489, 15465422, 30556376, 15937921, 12955717, 25764212, 24386122, 21228398, 27792009, 25558065, 27884173, 25099932)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000362578	SCV002570814	benign	not specified	2022-07-06	criteria provided, single submitter	clinical testing	Variant summary: NPC2 c.88G>A (p.Val30Met) results in a conservative amino acid change located in the MD-2-related lipid-recognition domain (IPR003172) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0021 in 207464 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in NPC2 causing Niemann-Pick Disease Type C phenotype (0.00068), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no penetrant association of c.88G>A with Niemann-Pick Disease Type C has been reported in the literature. A functional study examining the expression and localization of NPC2 missense variants in human fibroblasts found no biological abnormalities in cells expressing this variant, suggesting it does not strongly impact protein function (Chikh_2005). Seven assessments for this variant have been submitted to ClinVar after 2014 without evidence for independent evaluation and all classified the variant as benign (n=4) or likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign.
Fulgent Genetics, Fulgent Genetics	RCV001080727	SCV002806058	likely benign	Niemann-Pick disease, type C2	2021-10-17	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000675984	SCV004136891	likely benign	not provided	2024-11-01	criteria provided, single submitter	clinical testing	NPC2: BP4, BS2
Breakthrough Genomics, Breakthrough Genomics	RCV000675984	SCV005212549	likely benign	not provided		criteria provided, single submitter	not provided
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000162102	SCV000196387	likely pathogenic	Global developmental delay; Seizure; Microcephaly; Brain atrophy	2014-12-01	no assertion criteria provided	research
Mayo Clinic Laboratories, Mayo Clinic	RCV000675984	SCV000801716	likely benign	not provided	2017-12-19	no assertion criteria provided	clinical testing
Natera, Inc.	RCV001080727	SCV001461635	benign	Niemann-Pick disease, type C2	2020-04-18	no assertion criteria provided	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000675984	SCV001741169	likely benign	not provided		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000675984	SCV001807119	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000675984	SCV001968707	likely benign	not provided		no assertion criteria provided	clinical testing