ClinVar Genomic variation as it relates to human health
NM_004985.5(KRAS):c.108A>G (p.Ile36Met)
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_004985.5(KRAS):c.108A>G (p.Ile36Met)
Variation ID: 163768 Accession: VCV000163768.26
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 12p12.1 12: 25245277 (GRCh38) [ NCBI UCSC ] 12: 25398211 (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 Feb 2, 2015 Oct 8, 2024 Dec 20, 2022 - HGVS
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Nucleotide Protein Molecular
consequenceNM_004985.5:c.108A>G MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_004976.2:p.Ile36Met missense NM_033360.4:c.108A>G MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_203524.1:p.Ile36Met missense NM_001369786.1:c.108A>G NP_001356715.1:p.Ile36Met missense NM_001369787.1:c.108A>G NP_001356716.1:p.Ile36Met missense NC_000012.12:g.25245277T>C NC_000012.11:g.25398211T>C NG_007524.2:g.10727A>G LRG_344:g.10727A>G LRG_344t1:c.108A>G LRG_344p1:p.Ile36Met LRG_344t2:c.108A>G LRG_344p2:p.Ile36Met P01116:p.Ile36Met - Protein change
- I36M
- Other names
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- Canonical SPDI
- NC_000012.12:25245276:T:C
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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
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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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KRAS | No evidence available | No evidence available |
GRCh38 GRCh37 |
463 | 521 |
Conditions - Germline
Condition
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The condition for this variant-condition (RCV) record in ClinVar. |
Classification
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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
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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
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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 (2) |
criteria provided, multiple submitters, no conflicts
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Oct 1, 2022 | RCV000150891.11 | |
Likely pathogenic (5) |
criteria provided, multiple submitters, no conflicts
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Dec 20, 2022 | RCV000260877.8 | |
Likely pathogenic (1) |
criteria provided, single submitter
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Feb 15, 2018 | RCV000844636.4 | |
Pathogenic (1) |
criteria provided, single submitter
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- | RCV000856729.1 | |
Pathogenic (1) |
criteria provided, single submitter
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Feb 1, 2017 | RCV002444616.2 | |
KRAS-related disorder
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Pathogenic (1) |
no assertion criteria provided
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Nov 4, 2023 | RCV004551310.2 |
Submissions - Germline
Classification
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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
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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
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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
(Dec 20, 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: SCV000329772.8
First in ClinVar: Dec 06, 2016 Last updated: Dec 31, 2022 |
Comment:
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of … (more)
Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; The majority of missense variants in this gene are considered pathogenic (HGMD); This variant is associated with the following publications: (PMID: 30586318, 18470943, 21784453, 24803665, 25525159, 17056636, 18958496, 29493581, 35158933, 32240795, 17211612, 27104176) (less)
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Pathogenic
(Oct 01, 2022)
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criteria provided, single submitter
Method: clinical testing
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RASopathy
Affected status: unknown
Allele origin:
germline
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Labcorp Genetics (formerly Invitae), Labcorp
Accession: SCV000939441.6
First in ClinVar: Aug 14, 2019 Last updated: Feb 14, 2024 |
Comment:
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 36 of the KRAS protein (p.Ile36Met). … (more)
This sequence change replaces isoleucine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 36 of the KRAS protein (p.Ile36Met). 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 KRAS protein function. ClinVar contains an entry for this variant (Variation ID: 163768). This missense change has been observed in individual(s) with RASopathies spectrum (PMID: 17056636, 18958496, 21784453; 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). (less)
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Likely pathogenic
(Oct 25, 2018)
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criteria provided, single submitter
Method: clinical testing
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Rasopathy
Affected status: unknown
Allele origin:
germline
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Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Accession: SCV000919564.1
First in ClinVar: Jun 03, 2019 Last updated: Jun 03, 2019 |
Comment:
Variant summary: KRAS c.108A>G (p.Ile36Met) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. … (more)
Variant summary: KRAS c.108A>G (p.Ile36Met) results in a conservative amino acid change located in the Small GTP-binding protein domain (IPR005225) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 237482 control chromosomes (gnomAD). c.108A>G has been reported in the literature in individuals affected with Noonan Syndrome (Zenker 2007, Lo 2009, Lee 2011). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported; though an in vitro study demonstrated that substitutions of Ile36 caused severe impairment in Ras protein function, indicating the importance of this amino acid residue (Chung 1993). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both classified the variant as pathogenic (1x) / likely pathogenic (1x). Based on the evidence outlined above, the variant was classified as likely pathogenic. (less)
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Likely pathogenic
(Feb 23, 2018)
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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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Blueprint Genetics
Accession: SCV000927544.1
First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019
Comment:
Patient analyzed with Noonan Syndrome Panel
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Likely pathogenic
(Feb 15, 2018)
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criteria provided, single submitter
Method: clinical testing
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Noonan syndrome
Cardio-facio-cutaneous syndrome
Affected status: not provided
Allele origin:
germline
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Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000198471.4
First in ClinVar: Feb 02, 2015 Last updated: Feb 02, 2015 |
Comment:
proposed classification - variant undergoing re-assessment, contact laboratory
Number of individuals with the variant: 1
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Pathogenic
(-)
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criteria provided, single submitter
Method: clinical testing
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Cardiofaciocutaneous syndrome 1
Affected status: yes
Allele origin:
unknown
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Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn
Accession: SCV000999274.1
First in ClinVar: Dec 01, 2019 Last updated: Dec 01, 2019 |
Number of individuals with the variant: 1
Clinical Features:
High forehead (present) , Failure to thrive (present) , Delayed eruption of primary teeth (present) , Cafe-au-lait spot (present) , Bilateral ptosis (present) , Pectus … (more)
High forehead (present) , Failure to thrive (present) , Delayed eruption of primary teeth (present) , Cafe-au-lait spot (present) , Bilateral ptosis (present) , Pectus carinatum (present) , Posteriorly rotated ears (present) , Trigonocephaly (present) , Pulmonic stenosis (present) , Red hair (present) , Abnormality of hair density (present) , Ptosis (present) , Tented upper lip vermilion (present) , Narrow palpebral fissure (present) (less)
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Pathogenic
(Feb 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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Cardiovascular phenotype
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV002733242.2
First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024 |
Comment:
The p.I36M pathogenic mutation (also known as c.108A>G), located in coding exon 1 of the KRAS gene, results from an A to G substitution at … (more)
The p.I36M pathogenic mutation (also known as c.108A>G), located in coding exon 1 of the KRAS gene, results from an A to G substitution at nucleotide position 108. The isoleucine at codon 36 is replaced by methionine, an amino acid with similar properties. This variant has been reported in two unrelated individuals with clinical diagnoses of Noonan syndrome (Zenker M et al. J Med Genet. 2007;44(2):131-5; Lo FS et al. Eur J Pediatr. 2009;168(8):919-23). This amino acid substitution resulted in decreased GAP activation in vitro (Chung HH et al. Proc Natl Acad Sci U S A. 1993;90(21):10145-9). In addition, this mutation has been determined by our laboratory to be the result of a de novo event in one family in the setting of new disease. Based on the supporting evidence, p.I36M is interpreted as a disease-causing mutation. (less)
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Genome Diagnostics Laboratory, Amsterdam University Medical Center
Study: VKGL Data-share Consensus
Accession: SCV001808517.1 First in ClinVar: Aug 27, 2021 Last updated: Aug 27, 2021 |
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Pathogenic
(Nov 04, 2023)
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no assertion criteria provided
Method: clinical testing
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KRAS-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004759872.2
First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024 |
Comment:
The KRAS c.108A>G variant is predicted to result in the amino acid substitution p.Ile36Met. This variant has been reported as a recurrent finding in individuals … (more)
The KRAS c.108A>G variant is predicted to result in the amino acid substitution p.Ile36Met. This variant has been reported as a recurrent finding in individuals with Noonan syndrome (Zenker et al. 2007. PubMed ID: 17056636; Lo et al. 2009. PubMed ID: 18958496; Lee et al. 2011. PubMed ID: 21784453). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. (less)
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Pathogenic
(Sep 16, 2018)
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no assertion criteria provided
Method: research
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not provided
Affected status: yes
Allele origin:
germline
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Gharavi Laboratory, Columbia University
Accession: SCV000809220.1
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
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Pathogenic
(-)
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no assertion criteria provided
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Additional submitter:
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Study: VKGL Data-share Consensus
Accession: SCV001952076.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021 |
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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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Spectrum of mutations in Noonan syndrome and their correlation with phenotypes. | Lee BH | The Journal of pediatrics | 2011 | PMID: 21784453 |
Noonan syndrome caused by germline KRAS mutation in Taiwan: report of two patients and a review of the literature. | Lo FS | European journal of pediatrics | 2009 | PMID: 18958496 |
Expansion of the genotypic and phenotypic spectrum in patients with KRAS germline mutations. | Zenker M | Journal of medical genetics | 2007 | PMID: 17056636 |
Probing the role of loop 2 in Ras function with unnatural amino acids. | Chung HH | Proceedings of the National Academy of Sciences of the United States of America | 1993 | PMID: 8234268 |
Text-mined citations for rs727503109 ...
HelpRecord last updated Oct 13, 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.