Submissions for variant NM_000631.5(NCF4):c.647C>T (p.Thr216Met)

gnomAD frequency: 0.00064  dbSNP: rs146911421

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000648869	SCV000770690	uncertain significance	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3	2022-11-01	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 216 of the NCF4 protein (p.Thr216Met). This variant is present in population databases (rs146911421, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Crohn's disease (PMID: 29454792). ClinVar contains an entry for this variant (Variation ID: 341555). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Fulgent Genetics, Fulgent Genetics	RCV000648869	SCV002782592	uncertain significance	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3	2022-04-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003155166	SCV003844925	likely benign	not specified	2023-02-17	criteria provided, single submitter	clinical testing	Variant summary: NCF4 c.647C>T (p.Thr216Met) results in a non-conservative amino acid change located in the SH3 domain (IPR001452) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00061 in 249690 control chromosomes, predominantly at a frequency of 0.00093 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4 fold of the estimated maximal expected allele frequency for a pathogenic variant in NCF4 causing Chronic Granulomatous Disease phenotype (0.00025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.647C>T has been reported in the literature in one individual affected with inflammatory bowel diseases (Denson_2018). Thes reports does not provide unequivocal conclusions about association of the variant with Chronic Granulomatous Disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
PreventionGenetics, part of Exact Sciences	RCV003409547	SCV004114946	uncertain significance	NCF4-related disorder	2022-12-07	criteria provided, single submitter	clinical testing	The NCF4 c.647C>T variant is predicted to result in the amino acid substitution p.Thr216Met. This variant was reported in heterozygous state an individual with inflammatory bowel diseases (Denson et al 2018. PubMed ID: 29454792 Table 1). This variant is reported in 0.11% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/22-37271714-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
GenomeConnect - Brain Gene Registry	RCV000648869	SCV004012810	not provided	Granulomatous disease, chronic, autosomal recessive, cytochrome b-positive, type 3		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 06-14-2021 by Lab The Children's Hospital of Philadelphia. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/.