Submissions for variant NM_001042492.3(NF1):c.5293A>G (p.Thr1765Ala)

gnomAD frequency: 0.00001  dbSNP: rs747584987

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000466099	SCV000542054	uncertain significance	Neurofibromatosis, type 1	2024-01-31	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1744 of the NF1 protein (p.Thr1744Ala). This variant is present in population databases (rs747584987, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with NF1-related conditions. ClinVar contains an entry for this variant (Variation ID: 404477). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. 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.
Ambry Genetics	RCV002313155	SCV000663150	uncertain significance	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2023-01-17	criteria provided, single submitter	clinical testing	The p.T1744A variant (also known as c.5230A>G), located in coding exon 37 of the NF1 gene, results from an A to G substitution at nucleotide position 5230. The threonine at codon 1744 is replaced by alanine, an amino acid with similar properties. This variant has been detected in multiple individuals with no reported features of NF1-associated disease (Ambry internal data). 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 this alteration remains unclear.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000466099	SCV000782047	uncertain significance	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000679398	SCV000806294	uncertain significance	not provided	2017-11-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000679398	SCV000808685	uncertain significance	not provided	2023-07-25	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 27535533)
Johns Hopkins Genomics, Johns Hopkins University	RCV000466099	SCV001905479	uncertain significance	Neurofibromatosis, type 1	2021-08-24	criteria provided, single submitter	clinical testing	This NF1 variant (rs747584987) is rare (<0.1%) in a large population dataset (gnomAD: 2/251034 total alleles; 0.0008%; no homozygotes) and has been reported in ClinVar. It has not been reported in the literature, to our knowledge. Of three bioinformatics tools queried, two predict that the substitution would be damaging, while one predicts that it would be tolerated. The threonine residue at this position is evolutionarily conserved across all species assessed. We consider the clinical significance of NF1 c.5293A>G to be uncertain at this time.
Genome-Nilou Lab	RCV000466099	SCV002560533	uncertain significance	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003330685	SCV004038772	uncertain significance	not specified	2023-08-03	criteria provided, single submitter	clinical testing	Variant summary: NF1 c.5230A>G (p.Thr1744Ala) 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-06 in 251034 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.5230A>G in individuals affected with Neurofibromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.