NM_001042492.3(NF1):c.7910G>A (p.Arg2637Gln) AND not provided

Clinical significance:Conflicting interpretations of pathogenicity, Likely benign(1);Uncertain significance(2) (Last evaluated: Apr 18, 2018)

Review status:1 star out of maximum of 4 stars

criteria provided, conflicting interpretations

Based on:
3 submissions [Details]
Record status:
current
Accession:
RCV000679416.4

Allele description [Variation Report for NM_001042492.3(NF1):c.7910G>A (p.Arg2637Gln)]

NM_001042492.3(NF1):c.7910G>A (p.Arg2637Gln)

Gene:
NF1:neurofibromin 1 [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
17q11.2
Genomic location:
Preferred name:
NM_001042492.3(NF1):c.7910G>A (p.Arg2637Gln)
HGVS:
  • NC_000017.11:g.31357309G>A
  • NG_009018.1:g.267333G>A
  • NM_000267.3:c.7847G>A
  • NM_001042492.2:c.7910G>A
  • NM_001042492.3:c.7910G>AMANE SELECT
  • NP_000258.1:p.Arg2616Gln
  • NP_001035957.1:p.Arg2637Gln
  • NP_001035957.1:p.Arg2637Gln
  • LRG_214t1:c.7847G>A
  • LRG_214t2:c.7910G>A
  • LRG_214:g.267333G>A
  • LRG_214p1:p.Arg2616Gln
  • LRG_214p2:p.Arg2637Gln
  • NC_000017.10:g.29684327G>A
  • p.R2637Q
Protein change:
R2616Q
Links:
dbSNP: rs560262404
NCBI 1000 Genomes Browser:
rs560262404
Molecular consequence:
  • NM_000267.3:c.7847G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042492.2:c.7910G>A - missense variant - [Sequence Ontology: SO:0001583]
  • NM_001042492.3:c.7910G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Identifiers:
MedGen: CN517202

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Assertion and evidence details

Submission AccessionSubmitterReview Status
(Assertion method)
Clinical Significance
(Last evaluated)
OriginMethodCitations
SCV000806322PreventionGenetics,PreventionGeneticscriteria provided, single submitter
Uncertain significance
(Dec 11, 2017)
germlineclinical testing

PubMed (1)
[See all records that cite this PMID]

SCV000808670GeneDxcriteria provided, single submitter
Uncertain significance
(Apr 18, 2018)
germlineclinical testing

Citation Link,

SCV000884247ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratoriescriteria provided, single submitter
Likely benign
(Jun 16, 2017)
germlineclinical testing

Citation Link

Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineyesnot providednot providednot providednot providednot providedclinical testing
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]
PMID:
25741868
PMCID:
PMC4544753

Details of each submission

From PreventionGenetics,PreventionGenetics, SCV000806322.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (1)
#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

From GeneDx, SCV000808670.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

This variant is denoted NF1 c.7847G>A at the cDNA level, p.Arg2616Gln (R2616Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant was observed in a family with a clinical diagnosis of neurofibromatosis type 1; however, a pathogenic nonsense variant in NF1 was found to segregate with disease in this family (Messiaen 2000). This variant was also observed in two siblings with Asperger syndrome (Toma 2014). NF1 Arg2616Gln was observed at an allele frequency of 0.007% (8/111,574) in individuals of European ancestry in large population cohorts (Lek 2016). This variant is located in the C-terminal domain (Luo 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether NF1 Arg2616Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineyesnot providednot providednot providednot providednot providednot providednot provided

From ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories, SCV000884247.1

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testingnot provided

Description

The NF1 c.7910G>A; p.Arg2637Gln variant (rs560262404), also known as c.7847G>A; p.Arg2616Gln, has been reported in the literature in a patient who carries a pathogenic NF1 variant in trans, and did not segregate with disease in this family (Messiaen 2000). This variant is reported in ClinVar (Variation ID: 141130), and is observed in general population databases at frequencies of 0.02 percent (1/5008 alleles, 1000 Genome Project), and 0.007 percent (8/111574 alleles, Genome Aggregation Database). The arginine at codon 2637 is highly conserved, but computational algorithms do not agree as to the effect this variant may have on the protein (SIFT: Tolerated, PolyPhen2: Probably Damaging, MutationTaster: Disease Causing, Align GVGD: C0). Taken together, this variant is considered likely benign. REFERENCES Link to ClinVar database for p.Arg2637Gln: https://www.ncbi.nlm.nih.gov/clinvar/variation/141130/ Messiaen LM et al. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15(6):541-55.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: Nov 11, 2021

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