Submissions for variant NM_001042492.3(NF1):c.2342A>C (p.His781Pro)

dbSNP: rs199474763

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV004992006	SCV000277163	pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-08-13	criteria provided, single submitter	clinical testing	The p.H781P pathogenic mutation (also known as c.2342A>C), located in coding exon 20 of the NF1 gene, results from an A to C substitution at nucleotide position 2342. The histidine at codon 781 is replaced by proline, an amino acid with similar properties. This variant was reported in multiple individuals with features consistent with neurofibromatosis type 1 (Fahsold R et al. Am J Hum Genet, 2000 Mar;66:790-818; Calì F et al. Eur J Med Genet, 2017 Feb;60:93-99; Roka K et al. Pediatr Blood Cancer, 2023 Apr;:e30364). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002470751	SCV002767632	pathogenic	Neurofibromatosis, type 1	2020-06-11	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as pathogenic. Following criteria are met: 0102 - Loss-of-function is a known mechanism of disease for this gene. (N) 0107 - This gene is known to be associated with autosomal dominant disease. (N) 0200 - Variant is predicted to result in a missense amino acid change from histidine to proline (exon 20). (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (1 heterozygote, 0 homozygotes). (N) 0502 - Missense variant with conflicting in silico predictions and/or uninformative conservation. (N) 0604 - Variant is not located in an established domain, motif, hotspot or informative constraint region. (N) 0708 - Comparable variants (p.His781Arg, p.His781Leu) have been previously reported as VUS (ClinVar). (N) 0801 - Strong previous evidence of pathogenicity. This variant has been reported as a VUS (ClinVar) and pathogenic (LOVD), and has been observed in multiple de novo patients with neurofibromatosis type I (LOVD, PMID: 27838393, PMID: 10712197). (P) 0905 - No segregation evidence has been identified for this variant. (N) 1007 - No published functional evidence has been identified for this variant. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
GeneDx	RCV000059169	SCV004170602	likely pathogenic	not provided	2023-10-27	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24803665, 27838393, 10712197, 27535533, 25486365)
Labcorp Genetics (formerly Invitae), Labcorp	RCV002470751	SCV004297445	likely pathogenic	Neurofibromatosis, type 1	2023-04-17	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 781 of the NF1 protein (p.His781Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with neurofibromatosis type 1 (PMID: 10712197, 27838393). ClinVar contains an entry for this variant (Variation ID: 68317). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NF1 protein function. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
UniProtKB/Swiss-Prot	RCV000059169	SCV000090698	not provided	not provided		no assertion provided	not provided