ClinVar Genomic variation as it relates to human health
NM_001042492.3(NF1):c.528T>A (p.Asp176Glu)
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.
Uncertain significance(1); Benign(13); Likely benign(6)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_001042492.3(NF1):c.528T>A (p.Asp176Glu)
Variation ID: 41673 Accession: VCV000041673.58
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 17q11.2 17: 31169939 (GRCh38) [ NCBI UCSC ] 17: 29496957 (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 Apr 12, 2013 May 12, 2024 Apr 1, 2024 - HGVS
-
Nucleotide Protein Molecular
consequenceNM_001042492.3:c.528T>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001035957.1:p.Asp176Glu missense NM_000267.3:c.528T>A NP_000258.1:p.Asp176Glu missense NM_001042492.1:c.528T>A NM_001128147.3:c.528T>A NP_001121619.1:p.Asp176Glu missense NC_000017.11:g.31169939T>A NC_000017.10:g.29496957T>A NG_009018.1:g.79963T>A LRG_214:g.79963T>A LRG_214t1:c.528T>A LRG_214p1:p.Asp176Glu LRG_214t2:c.528T>A LRG_214p2:p.Asp176Glu P21359:p.Asp176Glu - Protein change
- D176E
- Other names
- -
- Canonical SPDI
- NC_000017.11:31169938:T:A
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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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0.00080 (A)
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Allele frequency
Help
The frequency of the allele represented by this VCV record.
1000 Genomes Project 30x 0.00062
1000 Genomes Project 0.00080
Trans-Omics for Precision Medicine (TOPMed) 0.00292
Exome Aggregation Consortium (ExAC) 0.00329
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00346
The Genome Aggregation Database (gnomAD), exomes 0.00348
The Genome Aggregation Database (gnomAD) 0.00398
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
Help
The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
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 |
13562 | 13971 |
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
Help
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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Benign/Likely benign (7) |
criteria provided, multiple submitters, no conflicts
|
Apr 1, 2024 | RCV000034585.33 | |
Benign (9) |
criteria provided, multiple submitters, no conflicts
|
Sep 16, 2020 | RCV000121638.35 | |
Benign (2) |
criteria provided, multiple submitters, no conflicts
|
Jul 15, 2020 | RCV000129680.10 | |
Conflicting interpretations of pathogenicity (5) |
criteria provided, conflicting classifications
|
Feb 1, 2024 | RCV000199175.33 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000268253.13 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000264802.13 | |
Likely benign (1) |
criteria provided, single submitter
|
Apr 27, 2017 | RCV000323382.13 |
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
Help
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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Benign
(Jan 03, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: not provided
Allele origin:
germline
|
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000510669.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
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Benign
(Oct 20, 2016)
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criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: no
Allele origin:
germline
|
Genetic Services Laboratory, University of Chicago
Accession: SCV000248163.2
First in ClinVar: Oct 05, 2015 Last updated: Nov 10, 2017 |
|
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Uncertain significance
(Nov 01, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
|
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Accession: SCV000781873.1
First in ClinVar: Dec 26, 2017 Last updated: Dec 26, 2017 |
|
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Benign
(Jun 22, 2015)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000269458.3
First in ClinVar: May 29, 2016 Last updated: Jun 02, 2019 |
Comment:
p.Asp176Glu in exon 5 of NF1: This variant is not expected to have clinical sign ificance because it has been identified in 1% (67/6564) of … (more)
p.Asp176Glu in exon 5 of NF1: This variant is not expected to have clinical sign ificance because it has been identified in 1% (67/6564) of Finnish chromosomes a nd 0.5% (307/66442) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs112306990). (less)
Number of individuals with the variant: 4
|
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Likely benign
(Apr 27, 2017)
|
criteria provided, single submitter
Method: clinical testing
|
Café-au-lait macules with pulmonary stenosis
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000401690.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis-Noonan syndrome
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000401692.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000401691.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
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Likely benign
(Apr 27, 2017)
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criteria provided, single submitter
Method: clinical testing
|
Neurofibromatosis, familial spinal
Affected status: unknown
Allele origin:
germline
|
Illumina Laboratory Services, Illumina
Accession: SCV000401689.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, … (more)
This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. (less)
|
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Benign
(Oct 26, 2020)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, The Hospital for Sick Children
Accession: SCV001478991.1
First in ClinVar: Feb 13, 2021 Last updated: Feb 13, 2021 |
|
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Benign
(Sep 16, 2020)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
unknown
|
Athena Diagnostics
Accession: SCV001879399.1
First in ClinVar: Sep 19, 2021 Last updated: Sep 19, 2021 |
|
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Benign
(Jul 15, 2020)
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criteria provided, single submitter
Method: curation
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Sema4, Sema4
Accession: SCV002527613.1
First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022 |
|
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Benign
(-)
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criteria provided, single submitter
Method: clinical testing
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NOT SPECIFIED
Affected status: unknown
Allele origin:
germline
|
PreventionGenetics, part of Exact Sciences
Accession: SCV000306277.1
First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016 |
|
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Benign
(May 24, 2016)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000521056.5
First in ClinVar: Mar 08, 2017 Last updated: Sep 21, 2018 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
|
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Benign
(Nov 27, 2017)
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criteria provided, single submitter
Method: clinical testing
|
not specified
Affected status: unknown
Allele origin:
germline
|
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000917883.1
First in ClinVar: Jun 02, 2019 Last updated: Jun 02, 2019 |
Comment:
Variant summary: The NF1 c.528T>A (p.Asp176Glu) variant involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 3/5 in silico tools. … (more)
Variant summary: The NF1 c.528T>A (p.Asp176Glu) variant involves the alteration of a non-conserved nucleotide and is predicted to be damaging by 3/5 in silico tools. This variant was found in 1021/277004 control chromosomes (gnomAD), predominantly observed in the European (Finnish) subpopulation at a frequency of 0.011683 (301/25764). This frequency is about 56 times the estimated maximal expected allele frequency of a pathogenic NF1 variant (0.0002084), suggesting this is likely a benign polymorphism found primarily in the populations of European (Finnish) origin. This variant has been reported in several patients with neurofibromatosis type 1, including evidence of lack of cosegregation with disease and co-occurrence with other pathogenic variants in the same gene (Fahsold_2000, Ars_2003, and Nemethova_2013), strongly supporting for the benign outcome. In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as benign. Taken together, this variant is classified as Benign. (less)
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Likely benign
(May 28, 2019)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
unknown
|
Mendelics
Accession: SCV001140338.1
First in ClinVar: Jan 13, 2020 Last updated: Jan 13, 2020 |
|
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Benign
(Jul 14, 2014)
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criteria provided, single submitter
Method: clinical testing
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Hereditary cancer-predisposing syndrome
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV000184479.5
First in ClinVar: Aug 06, 2014 Last updated: Mar 24, 2015 |
Comment:
Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Does not segregate with disease in family study (genes with incomplete penetrance);Other strong … (more)
Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;Does not segregate with disease in family study (genes with incomplete penetrance);Other strong data supporting benign classification (less)
Number of individuals with the variant: 1
|
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Benign
(Jul 23, 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: SCV000885828.3
First in ClinVar: Sep 21, 2018 Last updated: Jan 26, 2021 |
|
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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Neurofibromatosis, type 1
Affected status: unknown
Allele origin:
germline
|
Invitae
Accession: SCV000252687.11
First in ClinVar: Oct 11, 2015 Last updated: Feb 14, 2024 |
|
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Likely benign
(Nov 03, 2021)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden
Accession: SCV002011204.3
First in ClinVar: Nov 06, 2021 Last updated: Jul 16, 2023 |
|
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Benign
(Apr 01, 2024)
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criteria provided, single submitter
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV002498262.13
First in ClinVar: Apr 11, 2022 Last updated: May 12, 2024 |
Comment:
NF1: BS1, BS2
Number of individuals with the variant: 23
|
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Likely benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not provided
Affected status: yes
Allele origin:
germline
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Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV002036569.1 First in ClinVar: Dec 18, 2021 Last updated: Dec 18, 2021 |
|
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no known pathogenicity
(Jul 13, 2012)
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no assertion criteria provided
Method: research
|
not provided
Affected status: no
Allele origin:
germline
|
Biesecker Lab/Clinical Genomics Section, National Institutes of Health
Study: ClinSeq
Accession: SCV000043383.1 First in ClinVar: Apr 12, 2013 Last updated: Apr 12, 2013 |
Comment:
Converted during submission to Benign.
Number of individuals with the variant: 6
Comment on evidence:
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for … (more)
The study set was not selected for affection status in relation to any cancer. Pathogenicity categories were based on literature curation. See Pubmed ID:22703879 for details. (less)
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808697.1 First in ClinVar: Aug 25, 2021 Last updated: Aug 25, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001974058.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021 |
|
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Benign
(-)
|
no assertion criteria provided
Method: clinical testing
|
not specified
Affected status: yes
Allele origin:
germline
|
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001743315.3 First in ClinVar: Jul 07, 2021 Last updated: Sep 08, 2021 |
|
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not provided
(Sep 19, 2013)
|
no classification provided
Method: reference population
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AllHighlyPenetrant
Affected status: unknown
Allele origin:
germline
|
ITMI
Accession: SCV000085836.1
First in ClinVar: Jun 09, 2014 Last updated: Jun 09, 2014
Comment:
Please see associated publication for description of ethnicities
|
Observation 1:
Ethnicity/Population group: Whole_cohort
Observation 2:
Ethnicity/Population group: African
Observation 3:
Ethnicity/Population group: African_European
Observation 4:
Ethnicity/Population group: Central_Asian
Observation 5:
Ethnicity/Population group: East_Asian
Observation 6:
Ethnicity/Population group: European
Observation 7:
Ethnicity/Population group: Hispanic
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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 |
---|---|---|---|---|
Phenotypic expression of a spectrum of Neurofibromatosis Type 1 (NF1) mutations identified through NGS and MLPA. | Tsipi M | Journal of the neurological sciences | 2018 | PMID: 30308447 |
Genome sequencing uncovers phenocopies in primary progressive multiple sclerosis. | Jia X | Annals of neurology | 2018 | PMID: 29908077 |
A Children's Oncology Group and TARGET initiative exploring the genetic landscape of Wilms tumor. | Gadd S | Nature genetics | 2017 | PMID: 28825729 |
Germline variation in cancer-susceptibility genes in a healthy, ancestrally diverse cohort: implications for individual genome sequencing. | Bodian DL | PloS one | 2014 | PMID: 24728327 |
Thirty-nine novel neurofibromatosis 1 (NF1) gene mutations identified in Slovak patients. | Nemethova M | Annals of human genetics | 2013 | PMID: 23758643 |
Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. | Johnston JJ | American journal of human genetics | 2012 | PMID: 22703879 |
Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas. | Thomas L | European journal of human genetics : EJHG | 2012 | PMID: 22108604 |
Neurofibromatosis type 1-associated tumours: their somatic mutational spectrum and pathogenesis. | Laycock-van Spyk S | Human genomics | 2011 | PMID: 22155606 |
Mechanisms of loss of heterozygosity in neurofibromatosis type 1-associated plexiform neurofibromas. | Steinmann K | The Journal of investigative dermatology | 2009 | PMID: 18800150 |
Novel mutations in the NF1 gene in Czech patients with neurofibromatosis type 1. | Bendova S | Journal of molecular neuroscience : MN | 2007 | PMID: 17726231 |
Mutational targets in colorectal cancer cells with microsatellite instability. | Bertholon J | Familial cancer | 2006 | PMID: 16528606 |
Pitfalls of automated comparative sequence analysis as a single platform for routine clinical testing for NF1. | Messiaen LM | Journal of medical genetics | 2005 | PMID: 15863657 |
Novel and recurrent mutations in the NF1 gene in Italian patients with neurofibromatosis type 1. | De Luca A | Human mutation | 2004 | PMID: 15146469 |
Automated comparative sequence analysis identifies mutations in 89% of NF1 patients and confirms a mutation cluster in exons 11-17 distinct from the GAP related domain. | Mattocks C | Journal of medical genetics | 2004 | PMID: 15060124 |
Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. | Ars E | Journal of medical genetics | 2003 | PMID: 12807981 |
Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type. | Wang Q | Human genetics | 2003 | PMID: 12522551 |
Analysis of the NF1 gene by temperature gradient gel electrophoresis reveals a high incidence of mutations in exon 4b. | Toliat MR | Electrophoresis | 2000 | PMID: 10726756 |
Minor lesion mutational spectrum of the entire NF1 gene does not explain its high mutability but points to a functional domain upstream of the GAP-related domain. | Fahsold R | American journal of human genetics | 2000 | PMID: 10712197 |
Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. | Upadhyaya M | Human genetics | 1998 | PMID: 9654211 |
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Text-mined citations for rs112306990 ...
HelpRecord last updated Jun 02, 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.