p.Gly12Val (GGC>GTC): c.35 G>T in exon 2 of the HRAS gene (NM_005343.2). This mutation as well as other mutations leading to the G12V substitution have been reported in individuals with Costello syndrome (Burkitt-Wright et al., 2012). This mutation is associated with a very severe presentation that has been associated with death in the first weeks of life (Burkitt-Wright et al., 2012). The most common features of infants harboring this mutation are severe polyhydramnios, birth weight on or above the 90th percentile, birth occipitofrontal circumference (OFC) on or above the 90th percentile, coarsening of facial features, unusual hand position, unusual foot position, short neck, cardiac hypertrophy, ventilator dependence, death before 6 weeks postnatal age (Burkitt-Wright et al., 2012). In fact, >90% of pathogenic HRAS mutations alter the conserved glycine residues at positions 12 and 13 (Aoki et al., 2005; Gripp et al., 2006). The G12V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s).
ClinVar Genomic variation as it relates to human health
Help
- Interpretation:
-
Pathogenic
- Review status:
- criteria provided, multiple submitters, no conflicts
- Submissions:
- 10
- First in ClinVar:
- Feb 24, 2015
- Most recent Submission:
- Mar 4, 2023
- Last evaluated:
- Jan 7, 2022
- Accession:
- VCV000012600.8
- Variation ID:
- 12600
- Description:
- single nucleotide variant
Help
NM_005343.4(HRAS):c.35G>T (p.Gly12Val)
- Allele ID
- 27639
- Variant type
- single nucleotide variant
- Variant length
- 1 bp
- Cytogenetic location
- 11p15.5
- Genomic location
- 11: 534288 (GRCh38) GRCh38 UCSC
- 11: 534288 (GRCh37) GRCh37 UCSC
- HGVS
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_005343.4:c.35G>T MANE Select NP_005334.1:p.Gly12Val missense NM_176795.5:c.35G>T MANE Plus Clinical NP_789765.1:p.Gly12Val missense NM_001130442.3:c.35G>T NP_001123914.1:p.Gly12Val missense NM_001318054.2:c.-285G>T 5 prime UTR NC_000011.10:g.534288C>A NC_000011.9:g.534288C>A NG_007666.1:g.6263G>T LRG_506:g.6263G>T LRG_506t1:c.35G>T LRG_506p1:p.Gly12Val P01112:p.Gly12Val - Protein change
- G12V
- Other names
- p.G12V:GGC>GTA
- Canonical SPDI
- NC_000011.10:534287:C:A
- Functional consequence
- -
- Global minor allele frequency (GMAF)
- -
- Allele frequency
- -
- Links
- ClinGen: CA122545
- UniProtKB: P01112#VAR_006836
- OMIM: 190020.0001
- dbSNP: rs104894230
- VarSome
Help
Aggregate interpretations per condition
| Interpreted condition | Interpretation | Number of submissions | Review status | Last evaluated | Variation/condition record |
|---|---|---|---|---|---|
| Pathogenic | 4 | criteria provided, multiple submitters, no conflicts | Jan 7, 2022 | RCV000013432.34 | |
| Pathogenic | 1 | criteria provided, single submitter | Aug 31, 2016 | RCV000157912.1 | |
| Pathogenic | 1 | no assertion criteria provided | Apr 1, 2012 | RCV000013431.7 | |
| Pathogenic | 1 | no assertion criteria provided | Apr 1, 2012 | RCV000013433.27 | |
| Pathogenic | 1 | no assertion criteria provided | Apr 1, 2012 | RCV000032850.7 | |
| Likely pathogenic | 1 | no assertion criteria provided | Jul 14, 2015 | RCV000428111.1 | |
| Pathogenic | 1 | no assertion criteria provided | Oct 2, 2014 | RCV000438340.1 |
Submitted interpretations and evidence
Help| Interpretation (Last evaluated) |
Review status (Assertion criteria) |
Condition (Inheritance) |
Submitter | More information | |
|---|---|---|---|---|---|
|
Pathogenic
(Jun 04, 2014)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: yes
Allele origin:
unknown
|
Molecular Diagnostics Lab,Nemours Children's Health, Delaware
Accession: SCV000263055.1
First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015 |
Number of individuals with the variant: 1
Clinical Features:
Neonate with signs and symptoms of Cotello Syndrome (present)
Age: 0-9 years
Sex: male
|
|
|
Pathogenic
(Aug 31, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000207846.11
First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015 |
Comment:
p.Gly12Val (GGC>GTC): c.35 G>T in exon 2 of the HRAS gene (NM_005343.2). This mutation as well as other mutations leading to the G12V substitution have … (more)
p.Gly12Val (GGC>GTC): c.35 G>T in exon 2 of the HRAS gene (NM_005343.2). This mutation as well as other mutations leading to the G12V substitution have been reported in individuals with Costello syndrome (Burkitt-Wright et al., 2012). This mutation is associated with a very severe presentation that has been associated with death in the first weeks of life (Burkitt-Wright et al., 2012). The most common features of infants harboring this mutation are severe polyhydramnios, birth weight on or above the 90th percentile, birth occipitofrontal circumference (OFC) on or above the 90th percentile, coarsening of facial features, unusual hand position, unusual foot position, short neck, cardiac hypertrophy, ventilator dependence, death before 6 weeks postnatal age (Burkitt-Wright et al., 2012). In fact, >90% of pathogenic HRAS mutations alter the conserved glycine residues at positions 12 and 13 (Aoki et al., 2005; Gripp et al., 2006). The G12V mutation was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The variant is found in NOONAN panel(s). (less)
|
|
|
Pathogenic
(May 05, 2011)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: not provided
Allele origin:
germline
|
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Accession: SCV000062137.5
First in ClinVar: May 03, 2013 Last updated: Apr 30, 2017 |
Comment:
The Gly12Val variant in HRAS has been reported in the literature in a proband wi th Costello syndrome and was verified to have occured de … (more)
The Gly12Val variant in HRAS has been reported in the literature in a proband wi th Costello syndrome and was verified to have occured de novo in that individual (Aoki 2005). While the reported proband had an alternate DNA change (c.35_36del insTT), the predicted protein change is identical to that predicted for this pat ient. This Gly12Val variant is commonly seen as a somatic mutation in several ca ncers (Catalogue of Somatic Mutations in Cancer, http://www.sanger.ac.uk/cosmic) and functional studies have shown it to dramatically alter cell growth (Aoki 20 05). Therefore, this variant is highly likely to be pathogenic. (less)
Number of individuals with the variant: 1
|
|
|
Pathogenic
(Jan 07, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Costello syndrome
Affected status: unknown
Allele origin:
germline
|
PerkinElmer Genomics
Accession: SCV003825223.1
First in ClinVar: Mar 04, 2023 Last updated: Mar 04, 2023 |
|
|
|
Pathogenic
(Apr 01, 2012)
|
no assertion criteria provided
Method: literature only
|
EPIDERMAL NEVUS, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000056619.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, … (more)
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, while the same gene cloned from normal cellular DNA did not. Furthermore, they showed that the change in the transforming gene was a single nucleotide substitution that produced change of a single amino acid in the sequence of the protein that the gene encodes. They suggested that antibodies against Ras proteins might be diagnostic for certain forms of cancer. The T24 gene had a change from GGC (glycine) to GTC (valine) as codon 12. Fearon et al. (1985) examined constitutional and tumor genotypes at loci on the short arm of chromosome 11 in 12 patients with transitional cell carcinomas of the bladder. In 5 they found loss of genes in the tumor, resulting in homozygosity or hemizygosity of the remaining allele. This frequency (42%) approached that seen in Wilms tumor (55%). The G12V mutant of HRAS had the lowest GTPase activity among various substitutions at codon 12 (Colby et al., 1986), and biologic assays by focus formation in NIH3T3 cells or soft agar growth showed that this substitution had the highest transformation potential among substitutions tested at this codon (Seeburg et al., 1984, Fasano et al., 1984). Aoki et al. (2005) noted that among codon 12 HRAS mutations found somatically in human cancers, G12V is the predominant mutation. Epidermal Nevus, Somatic Hafner et al. (2012) identified a somatic G12V mutation in 1 of 72 keratinocytic epidermal nevi (162900). Costello Syndrome In a Japanese patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35GC-TT nucleotide substitution in the HRAS gene that resulted in a gly12-to-val amino acid change (G12V). This individual died of severe cardiomyopathy at 18 months of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12V mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a variant of Costello syndrome. The patient, originally reported by de Boode et al. (1996), died at age 3 weeks. He was a preterm infant with generalized hypotonia and progressive hypertrophic obstructive cardiomyopathy. (less)
|
|
|
Likely pathogenic
(Jul 14, 2015)
|
no assertion criteria provided
Method: literature only
|
Melanoma
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504410.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Oct 02, 2014)
|
no assertion criteria provided
Method: literature only
|
Thyroid tumor
(Somatic mutation)
Affected status: yes
Allele origin:
somatic
|
Database of Curated Mutations (DoCM)
Accession: SCV000504411.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
|
|
|
Pathogenic
(Apr 01, 2012)
|
no assertion criteria provided
Method: literature only
|
MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000033680.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, … (more)
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, while the same gene cloned from normal cellular DNA did not. Furthermore, they showed that the change in the transforming gene was a single nucleotide substitution that produced change of a single amino acid in the sequence of the protein that the gene encodes. They suggested that antibodies against Ras proteins might be diagnostic for certain forms of cancer. The T24 gene had a change from GGC (glycine) to GTC (valine) as codon 12. Fearon et al. (1985) examined constitutional and tumor genotypes at loci on the short arm of chromosome 11 in 12 patients with transitional cell carcinomas of the bladder. In 5 they found loss of genes in the tumor, resulting in homozygosity or hemizygosity of the remaining allele. This frequency (42%) approached that seen in Wilms tumor (55%). The G12V mutant of HRAS had the lowest GTPase activity among various substitutions at codon 12 (Colby et al., 1986), and biologic assays by focus formation in NIH3T3 cells or soft agar growth showed that this substitution had the highest transformation potential among substitutions tested at this codon (Seeburg et al., 1984, Fasano et al., 1984). Aoki et al. (2005) noted that among codon 12 HRAS mutations found somatically in human cancers, G12V is the predominant mutation. Epidermal Nevus, Somatic Hafner et al. (2012) identified a somatic G12V mutation in 1 of 72 keratinocytic epidermal nevi (162900). Costello Syndrome In a Japanese patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35GC-TT nucleotide substitution in the HRAS gene that resulted in a gly12-to-val amino acid change (G12V). This individual died of severe cardiomyopathy at 18 months of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12V mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a variant of Costello syndrome. The patient, originally reported by de Boode et al. (1996), died at age 3 weeks. He was a preterm infant with generalized hypotonia and progressive hypertrophic obstructive cardiomyopathy. (less)
|
|
|
Pathogenic
(Apr 01, 2012)
|
no assertion criteria provided
Method: literature only
|
BLADDER CANCER, SOMATIC
Affected status: not provided
Allele origin:
somatic
|
OMIM
Accession: SCV000033678.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, … (more)
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, while the same gene cloned from normal cellular DNA did not. Furthermore, they showed that the change in the transforming gene was a single nucleotide substitution that produced change of a single amino acid in the sequence of the protein that the gene encodes. They suggested that antibodies against Ras proteins might be diagnostic for certain forms of cancer. The T24 gene had a change from GGC (glycine) to GTC (valine) as codon 12. Fearon et al. (1985) examined constitutional and tumor genotypes at loci on the short arm of chromosome 11 in 12 patients with transitional cell carcinomas of the bladder. In 5 they found loss of genes in the tumor, resulting in homozygosity or hemizygosity of the remaining allele. This frequency (42%) approached that seen in Wilms tumor (55%). The G12V mutant of HRAS had the lowest GTPase activity among various substitutions at codon 12 (Colby et al., 1986), and biologic assays by focus formation in NIH3T3 cells or soft agar growth showed that this substitution had the highest transformation potential among substitutions tested at this codon (Seeburg et al., 1984, Fasano et al., 1984). Aoki et al. (2005) noted that among codon 12 HRAS mutations found somatically in human cancers, G12V is the predominant mutation. Epidermal Nevus, Somatic Hafner et al. (2012) identified a somatic G12V mutation in 1 of 72 keratinocytic epidermal nevi (162900). Costello Syndrome In a Japanese patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35GC-TT nucleotide substitution in the HRAS gene that resulted in a gly12-to-val amino acid change (G12V). This individual died of severe cardiomyopathy at 18 months of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12V mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a variant of Costello syndrome. The patient, originally reported by de Boode et al. (1996), died at age 3 weeks. He was a preterm infant with generalized hypotonia and progressive hypertrophic obstructive cardiomyopathy. (less)
|
|
|
Pathogenic
(Apr 01, 2012)
|
no assertion criteria provided
Method: literature only
|
COSTELLO SYNDROME
Affected status: not provided
Allele origin:
unknown
|
OMIM
Accession: SCV000033679.4
First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018 |
Comment on evidence:
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, … (more)
Bladder Cancer, Somatic Taparowsky et al. (1982) found that the HRAS1 gene cloned from a human bladder cancer cell line (T24) transformed NIH 3T3 cells, while the same gene cloned from normal cellular DNA did not. Furthermore, they showed that the change in the transforming gene was a single nucleotide substitution that produced change of a single amino acid in the sequence of the protein that the gene encodes. They suggested that antibodies against Ras proteins might be diagnostic for certain forms of cancer. The T24 gene had a change from GGC (glycine) to GTC (valine) as codon 12. Fearon et al. (1985) examined constitutional and tumor genotypes at loci on the short arm of chromosome 11 in 12 patients with transitional cell carcinomas of the bladder. In 5 they found loss of genes in the tumor, resulting in homozygosity or hemizygosity of the remaining allele. This frequency (42%) approached that seen in Wilms tumor (55%). The G12V mutant of HRAS had the lowest GTPase activity among various substitutions at codon 12 (Colby et al., 1986), and biologic assays by focus formation in NIH3T3 cells or soft agar growth showed that this substitution had the highest transformation potential among substitutions tested at this codon (Seeburg et al., 1984, Fasano et al., 1984). Aoki et al. (2005) noted that among codon 12 HRAS mutations found somatically in human cancers, G12V is the predominant mutation. Epidermal Nevus, Somatic Hafner et al. (2012) identified a somatic G12V mutation in 1 of 72 keratinocytic epidermal nevi (162900). Costello Syndrome In a Japanese patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35GC-TT nucleotide substitution in the HRAS gene that resulted in a gly12-to-val amino acid change (G12V). This individual died of severe cardiomyopathy at 18 months of age. Congenital Myopathy with Excess of Muscle Spindles Van der Burgt et al. (2007) identified a heterozygous G12V mutation in the HRAS gene in a patient with congenital myopathy with excess of muscle spindles (see 218040), a variant of Costello syndrome. The patient, originally reported by de Boode et al. (1996), died at age 3 weeks. He was a preterm infant with generalized hypotonia and progressive hypertrophic obstructive cardiomyopathy. (less)
|
Functional evidence
Help| 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 this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Prospective enterprise-level molecular genotyping of a cohort of cancer patients. | MacConaill LE | The Journal of molecular diagnostics : JMD | 2014 | PMID: 25157968 |
| Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. | Ho AL | The New England journal of medicine | 2013 | PMID: 23406027 |
| Keratinocytic epidermal nevi are associated with mosaic RAS mutations. | Hafner C | Journal of medical genetics | 2012 | PMID: 22499344 |
| Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. | Hoftijzer H | European journal of endocrinology | 2009 | PMID: 19773371 |
| Phase II trial of sorafenib in metastatic thyroid cancer. | Kloos RT | Journal of clinical oncology : official journal of the American Society of Clinical Oncology | 2009 | PMID: 19255327 |
| Myopathy caused by HRAS germline mutations: implications for disturbed myogenic differentiation in the presence of constitutive HRas activation. | van der Burgt I | Journal of medical genetics | 2007 | PMID: 17412879 |
| Hyperactive Ras in developmental disorders and cancer. | Schubbert S | Nature reviews. Cancer | 2007 | PMID: 17384584 |
| Germline mutations in HRAS proto-oncogene cause Costello syndrome. | Aoki Y | Nature genetics | 2005 | PMID: 16170316 |
| Myopathology in patients with a Noonan phenotype. | de Boode WP | Acta neuropathologica | 1996 | PMID: 8960317 |
| Biochemical characterization of polypeptides encoded by mutated human Ha-ras1 genes. | Colby WW | Molecular and cellular biology | 1986 | PMID: 3537694 |
| Loss of genes on the short arm of chromosome 11 in bladder cancer. | Fearon ER | Nature | 1985 | PMID: 2999610 |
| Analysis of the transforming potential of the human H-ras gene by random mutagenesis. | Fasano O | Proceedings of the National Academy of Sciences of the United States of America | 1984 | PMID: 6330729 |
| Biological properties of human c-Ha-ras1 genes mutated at codon 12. | Seeburg PH | Nature | 1984 | PMID: 6092966 |
| Activation of the T24 bladder carcinoma transforming gene is linked to a single amino acid change. | Taparowsky E | Nature | 1982 | PMID: 7177195 |
| http://docm.genome.wustl.edu/variants/ENST00000311189:c.35G>T | - | - | - | - |
Text-mined citations for rs104894230...
HelpThese citations are identified by LitVar using
the rs number, so they may include citations for more than one variant
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variant of interest.
Record last updated Mar 26, 2023