Submissions for variant NM_001042492.3(NF1):c.4958G>A (p.Arg1653His)

gnomAD frequency: 0.00002  dbSNP: rs763413441

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000213730	SCV000276861	uncertain significance	Hereditary cancer-predisposing syndrome	2015-06-29	criteria provided, single submitter	clinical testing	The p.R1653H variant (also known as c.4958G>A), located in coding exon 37 of the NF1 gene, results from a G to A substitution at nucleotide position 4958. The arginine at codon 1653 is replaced by histidine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 55000alleles tested) in our clinical cohort.This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis.Since supporting evidence is limited at this time, the clinical significance of p.R1653Hremains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001037911	SCV001201347	likely benign	Neurofibromatosis, type 1	2024-06-25	criteria provided, single submitter	clinical testing
Athena Diagnostics	RCV001658035	SCV001879397	uncertain significance	not provided	2020-10-09	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV001037911	SCV002560489	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235144	SCV003934409	uncertain significance	not specified	2023-05-08	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.4895G>A (p.Arg1632His) results in a non-conservative amino acid change located in the CRAL-TRIO lipid binding domain (IPR001251) 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 2e-05 in 251352 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.4895G>A in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Ambry Genetics	RCV004558539	SCV005048261	likely benign	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-06-09	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.
Fulgent Genetics, Fulgent Genetics	RCV005016598	SCV005646767	uncertain significance	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-05-22	criteria provided, single submitter	clinical testing