Submissions for variant NM_182641.4(BPTF):c.6035T>C (p.Ile2012Thr)

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV002985563	SCV003292342	uncertain significance	not provided	2023-08-17	criteria provided, single submitter	clinical testing	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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 2077514). This variant has not been reported in the literature in individuals affected with BPTF-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2138 of the BPTF protein (p.Ile2138Thr).
Ambry Genetics	RCV002976534	SCV003696949	likely benign	Inborn genetic diseases	2022-05-31	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
The Morris Kahn Laboratory of Human Genetics, Ben-Gurion University of the Negev	RCV003883206	SCV004232431	established risk allele	Kaposi sarcoma	2024-01-06	no assertion criteria provided	research	We demonstrate through genetic studies that a dominantly-inherited p.I2012T missense mutation in BPTF segregates with a phenotype of classical KS in seven immunocompetent individuals individuals in two families. Using an rKSHV.219-infected CRISPR/cas9-model, we show that BPTFI2012T mutant cells exhibit higher latent-to-lytic ratio, decreased virion production, increased LANA staining, and latent phenotype in viral transcriptomics. RNA-sequencing demonstrated that KSHV infection dysregulated oncogenic-like response and P53 pathways, MAPK cascade and blood vessel development pathways, consistent with KS. BPTFI2012T also enriched pathways of viral genome regulation and replication, immune response, and chemotaxis, including downregulation of IFI16, SHFL HLAs, TGFB1 and HSPA5, all previously associated with KSHV infection and tumorigenesis. Many of the differentially-expressed genes are regulated by Rel-NF-κB, which regulates immune processes, cell survival and proliferation and is pivotal to oncogenesis
OMIM	RCV004587403	SCV005077824	risk factor	Kaposi sarcoma, susceptibility to	2024-07-10	no assertion criteria provided	literature only