Submissions for variant NM_001042492.3(NF1):c.3445A>G (p.Met1149Val)

dbSNP: rs1187097568

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000632403	SCV000753582	pathogenic	Neurofibromatosis, type 1	2023-03-19	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Met1149 amino acid residue in NF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16944272, 27322474; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. ClinVar contains an entry for this variant (Variation ID: 527517). This missense change has been observed in individuals with clinical features of neurofibromatosis type 1 (PMID: 23656349, 24711935, 28706617, 31595648; Invitae). This variant is present in population databases (no rsID available, gnomAD 0.004%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1149 of the NF1 protein (p.Met1149Val).
Center for Human Genetics, Inc, Center for Human Genetics, Inc	RCV000632403	SCV000781984	likely pathogenic	Neurofibromatosis, type 1	2016-11-01	criteria provided, single submitter	clinical testing
Medical Genomics Laboratory, Department of Genetics UAB	RCV000632403	SCV000999177	pathogenic	Neurofibromatosis, type 1	2019-06-05	criteria provided, single submitter	clinical testing
GeneDx	RCV001591409	SCV001816297	pathogenic	not provided	2023-03-30	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate a damaging effect: impaired ability to inhibit GTP-Ras activity (Long et al., 2022); This variant is associated with the following publications: (PMID: 23656349, 26681766, 28706617, 24711935, 29617658, 29095814, 31618753, 31370276, 25486365, 2121369, 22807134, 27322474, 29290338, 16944272, 31776437, 31595648, 33884301, 34694046)
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV001591409	SCV002011207	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV002060718	SCV002495861	pathogenic	Neurofibromatosis, familial spinal; Juvenile myelomonocytic leukemia; Neurofibromatosis, type 1; Neurofibromatosis-Noonan syndrome; Café-au-lait macules with pulmonary stenosis	2021-03-30	criteria provided, single submitter	clinical testing	NF1 NM_000267.3 exon 26 p.Met1149Val (c.3445A>G): This variant has been reported in the literature in multiple individuals with features of neurofibromatosis type I, segregating with disease in several affected family members (van Minkelen 2014 PMID:23656349, Domingues 2014 PMID:24711935, Koczkowska 2020 PMID:31595648). This variant is not present in large control databases but is present in ClinVar, with several labs classifying this variant as pathogenic or likely pathogenic (Variation ID:527517). Evolutionary conservation and computational predictive tools suggest that this variant may impact the protein. Additionally, splice prediction tools suggest that this variant may affect splicing. However, further studies are needed to understand its impact. In summary, this variant is classified as pathogenic based on the data above.
Genome-Nilou Lab	RCV000632403	SCV002559956	likely pathogenic	Neurofibromatosis, type 1	2022-03-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002458006	SCV002617139	likely pathogenic	Hereditary cancer-predisposing syndrome; Cardiovascular phenotype	2017-05-31	criteria provided, single submitter	clinical testing	The p.M1149V variant (also known as c.3445A>G), located in coding exon 26 of the NF1 gene, results from an A to G substitution at nucleotide position 3445. The methionine at codon 1149 is replaced by valine, an amino acid with highly similar properties. In one study, this alteration was detected in an individual who met diagnostic criteria for Neurofibromatosis type 1 (NF1) and also carried a diagnosis of respiratory chain complex I deficiency (van Minkelen R et al. Clin. Genet., 2014 Apr;85:318-27). In another study, this alteration was detected in one individual from a cohort of NF1 patients, but it is unclear whether this individual met diagnostic criteria for NF1 (Domingues S et al. Case Rep Genet, 2014 Mar;2014:423071). A different alteration located at the same position, p.M1149I, was detected as a de novo occurrence in one individual; however, it is unclear whether this individual met diagnostic criteria for NF1 (Griffiths S et al. Fam. Cancer, 2007;6:21-34). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Illumina Laboratory Services, Illumina	RCV000632403	SCV002762684	pathogenic	Neurofibromatosis, type 1	2022-05-05	criteria provided, single submitter	clinical testing	The NF1 c.3445A>G (p.Met1149Val) variant results in the substitution of a methionine at amino acid position 1149 with valine. This variant has been reported in at least 38 heterozygous individuals with neurofibromatosis type 1 (Koczkowska et al. 2020). This variant is reported in the Genome Aggregation Database in one allele at a frequency of 0.000046 in the European (Finnish) population (version 2.1.1). The Met1149 residue has been identified as a non-truncating hotspot in the gene (Koczkowska et al. 2020) with additional pathogenic variants that have been identified in patients with neurofibromatosis type 1 within two residues on each side of the variant. Three other amino acid changes due to missense variants at the Met1149 residue that have been reported in the literature and found in at least 13 individuals with neurofibromatosis type 1 (Koczkowska et al. 2020). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. Based on the available evidence, the c.3445A>G (p.Met1149Val) variant is classified as pathogenic for neurofibromatosis type 1.
PreventionGenetics, part of Exact Sciences	RCV004547783	SCV004114806	pathogenic	NF1-related disorder	2023-03-07	criteria provided, single submitter	clinical testing	The NF1 c.3445A>G variant is predicted to result in the amino acid substitution p.Met1149Val. This missense variant has been documented in several individuals with neurofibromatosis type 1 (Domingues et al. 2014. PubMed ID: 24711935; Gengel et al. 2017. PubMed ID: 28706617; Koczkowska et al. 2020. PubMed ID: 31595648). In addition, alternative missense changes at the same codon (p.Met1149Thr, p.Met1149Ile) have been documented to be pathogenic individuals with neurofibromatosis type 1 (Koczkowska et al. 2020. PubMed ID: 31595648; Evans et al. 2016. PubMed ID: 27322474; Griffiths et al. 2007. PubMed ID: 16944272) and are interpreted as pathogenic/likely pathogenic in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/527517/). This variant is reported in 0.0046% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/17-29559848-A-G). This variant is interpreted as pathogenic.