ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.3447G>T (p.Met1149Ile)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001042492.3(NF1):c.3447G>T (p.Met1149Ile)
Variation ID: 457650 Accession: VCV000457650.15
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q11.2 17: 31232832 (GRCh38) [ NCBI UCSC ] 17: 29559850 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Dec 26, 2017 Feb 20, 2024 May 26, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_001042492.3:c.3447G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Met1149Ile missense NM_000267.3:c.3447G>T NP_000258.1:p.Met1149Ile missense NC_000017.11:g.31232832G>T NC_000017.10:g.29559850G>T NG_009018.1:g.142856G>T LRG_214:g.142856G>T LRG_214t1:c.3447G>T LRG_214p1:p.Met1149Ile - Protein change
- M1149I
- Other names
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- Canonical SPDI
- NC_000017.11:31232831:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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Allele frequency
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The frequency of the allele represented by this VCV record.
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Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
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The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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NF1 | Sufficient evidence for dosage pathogenicity | No evidence available |
GRCh38 GRCh38 GRCh37 |
13569 | 13970 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic/Likely pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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May 26, 2023 | RCV000542239.14 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Oct 31, 2018 | RCV000762987.10 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Aug 12, 2022 | RCV001811032.13 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
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This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely pathogenic
(Oct 31, 2018)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Neurofibromatosis, familial spinal Café-au-lait macules with pulmonary stenosis Neurofibromatosis-Noonan syndrome Juvenile myelomonocytic leukemia
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV000893432.1
First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019 |
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Pathogenic
(Jun 05, 2019)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
inherited
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Medical Genomics Laboratory, Department of Genetics UAB
Accession: SCV000999181.1
First in ClinVar: Nov 26, 2019 Last updated: Nov 26, 2019 |
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Pathogenic
(May 08, 2020)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Accession: SCV001473663.1
First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021 |
Comment:
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 … (more)
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. (less)
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Likely pathogenic
(Mar 15, 2022)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: no
Allele origin:
germline
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Genome-Nilou Lab
Accession: SCV002559958.1
First in ClinVar: Aug 23, 2022 Last updated: Aug 23, 2022 |
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Pathogenic
(Aug 12, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV003805212.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
Comment:
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 … (more)
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) (less)
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Pathogenic
(May 26, 2023)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000628522.3
First in ClinVar: Dec 26, 2017 Last updated: Feb 20, 2024 |
Comment:
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, … (more)
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). (less)
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Clinical spectrum of individuals with pathogenic NF1 missense variants affecting p.Met1149, p.Arg1276, and p.Lys1423: genotype-phenotype study in neurofibromatosis type 1. | Koczkowska M | Human mutation | 2020 | PMID: 31595648 |
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. | Evans DG | EBioMedicine | 2016 | PMID: 27322474 |
Molecular diagnosis of neurofibromatosis type 1: 2 years experience. | Griffiths S | Familial cancer | 2007 | PMID: 16944272 |
Text-mined citations for rs1064794277 ...
HelpRecord last updated Mar 23, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.