Submissions for variant NM_001042492.3(NF1):c.1658A>G (p.His553Arg)

dbSNP: rs1064794274

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480683	SCV000568602	likely pathogenic	not provided	2024-01-08	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: 16199547, 16944272, 20655465, 17879440, 27390349, 28862263, 31766501, 24803665, 31717729, 34392670, 36289852, 27838393, 25486365, 31370276, 27322474)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000632424	SCV000753604	pathogenic	Neurofibromatosis, type 1	2025-01-12	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 553 of the NF1 protein (p.His553Arg). 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: 16944272, 27322474, 27838393). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 420076). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt NF1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000632424	SCV000781925	pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000632424	SCV002561687	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002402394	SCV002706043	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2024-07-26	criteria provided, single submitter	clinical testing	The p.H553R variant (also known as c.1658A>G), located in coding exon 15 of the NF1 gene, results from an A to G substitution at nucleotide position 1658. The histidine at codon 553 is replaced by arginine, an amino acid with highly similar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with NF1-related disease (Ambry internal data; Yao R et al. Genes (Basel), 2019 10;10; Demir Gündoan B et al. Turk J Med Sci, 2021 Aug). This amino acid position is highly 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 majority of available evidence to date, this variant is likely to be pathogenic.
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV000632424	SCV005442184	pathogenic	Neurofibromatosis, type 1	2024-12-19	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV005018800	SCV005646696	likely pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2024-04-01	criteria provided, single submitter	clinical testing