Submissions for variant NM_001042492.3(NF1):c.3447G>T (p.Met1149Ile)

dbSNP: rs1064794277

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000542239	SCV000628522	pathogenic	Neurofibromatosis, type 1	2023-05-26	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. 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. ClinVar contains an entry for this variant (Variation ID: 457650). This missense change has been observed in individual(s) with neurofibromatosis type 1 (NF1) (PMID: 16944272, 27322474; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1149 of the NF1 protein (p.Met1149Ile).
Fulgent Genetics, Fulgent Genetics	RCV000762987	SCV000893432	likely pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2018-10-31	criteria provided, single submitter	clinical testing
Medical Genomics Laboratory, Department of Genetics UAB	RCV000542239	SCV000999181	pathogenic	Neurofibromatosis, type 1	2019-06-05	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV001811032	SCV001473663	pathogenic	not provided	2020-05-08	criteria provided, single submitter	clinical testing	The NF1 c.3447G>T; p.Met1149Ile variant (rs1064794277) is reported in the literature in two individuals affected with neurofibromatosis type 1 (NF1) (Koczkowska 2020). This variant is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The methionine at codon 1149 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Two other variants leading to the same p.Met1149Ile amino acid substitution (c.3447G>A and c.3447G>C) have been reported in multiple individuals affected with NF1 (Evans 2016, Griffiths 2007, Koczkowska 2020), including a de novo occurrence of the c.3447G>A variant (Griffiths 2007). Further, other missense variants at the same codon (p.Met1149Leu, p.Met1149Thr, p.Met1149Val) have been reported in individuals affected with NF1 and are also considered disease-causing (Koczkowska 2020). Based on available information, the c.3447G>T; p.Met1149Ile variant is considered to be pathogenic. References: Evans DG et al. Comprehensive RNA Analysis of the NF1 Gene in Classically Affected NF1 Affected Individuals Meeting NIH Criteria has High Sensitivity and Mutation Negative Testing is Reassuring in Isolated Cases With Pigmentary Features Only. EBioMedicine. 2016 May;7:212-20. Griffiths S et al. Molecular diagnosis of neurofibromatosis type 1: 2 years experience. Fam Cancer. 2007;6(1):21-34. Koczkowska M et al. Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. Hum Mutat. 2020 Jan;41(1):299-315.
Genome-Nilou Lab	RCV000542239	SCV002559958	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
GeneDx	RCV001811032	SCV003805212	pathogenic	not provided	2022-08-12	criteria provided, single submitter	clinical testing	Missense variants at residue Met1149, including two other substitutions leading to p.Met1149Ile (c.3447G>A and c.3447G>C), are associated with reduced risk of NF1-associated tumors and increased occurrence of Noonan syndrome-related features (Koczkowska et al., 2020); Reported to segregate with unspecified NF1-associated features in a family (Koczkowska et al., 2020); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25486365, 2121369, 22807134, 29290338, 34928431, 31595648)