Submissions for variant NM_001042492.3(NF1):c.2294G>A (p.Arg765His)

gnomAD frequency: 0.00002  dbSNP: rs199474777

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000197680	SCV000254487	likely benign	Neurofibromatosis, type 1	2023-12-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000221393	SCV000277121	uncertain significance	Hereditary cancer-predisposing syndrome	2015-07-13	criteria provided, single submitter	clinical testing	The p.R765H variant (also known as c.2294G>A), located in coding exon 19 of the NF1 gene, results from a G to A substitution at nucleotide position 2294.This variant was reported in one NF1 patient but not in affected relatives(Abernathy CR, et al. Hum.Mutat. 1997 ; 9(6):548-54). The arginine at codon 765 is replaced by histidine, an amino acid with highly similar properties. This variant was previously reported in the SNPDatabase as rs199474777.To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than55000 alleles tested) in our clinical cohort. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive.Since supporting evidence for this variant is limited at this time, the clinical significance ofp.R765Hremains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000197680	SCV000781945	uncertain significance	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000197680	SCV000803602	uncertain significance	Neurofibromatosis, type 1	2018-05-31	criteria provided, single submitter	curation	This variant is interpreted as a Uncertain Significance - Insufficient Evidence, for Neurofibromatosis 1, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder.
GeneDx	RCV000059165	SCV000808282	likely benign	not provided	2019-08-05	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 9195229, 10336779, 24448499)
The Laboratory of Genetics and Metabolism, Hunan Children’s Hospital	RCV001009580	SCV001169681	uncertain significance	Neurofibromatosis, type 1; Tibial pseudarthrosis	2018-11-10	criteria provided, single submitter	research
CeGaT Center for Human Genetics Tuebingen	RCV000059165	SCV001500110	likely benign	not provided	2023-10-01	criteria provided, single submitter	clinical testing	NF1: BS2
Sema4, Sema4	RCV000221393	SCV002527456	likely benign	Hereditary cancer-predisposing syndrome	2020-11-12	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002265591	SCV002547942	likely benign	not specified	2022-05-10	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.2294G>A (p.Arg765His) results in a non-conservative amino acid change in 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 8e-05 in 250754 control chromosomes, predominantly at a frequency of 0.00082 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 4-fold of the estimated maximal expected allele frequency for a pathogenic variant in NF1 causing Neurofibromatosis Type 1 phenotype (0.00021), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.2294G>A has been reported in the literature poorly segregating in individuals affected with Neurofibromatosis Type 1 within a family (e.g. Abernathy_1997, Krkljus_1998), while it was also reported in individuals unaffected with NF1 (Zhu_2019, Dorling_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submitters have assessed the variant since 2014: five classified the variant as of uncertain significance and two as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002444523	SCV002733931	benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2022-01-12	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
UniProtKB/Swiss-Prot	RCV000059165	SCV000090694	not provided	not provided		no assertion provided	not provided