VCV000012600.14 - ClinVar

NM_005343.4(HRAS):c.35G>T (p.Gly12Val)

Germline

Classification

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.

(13)

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.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005343.4(HRAS):c.35G>T (p.Gly12Val)

Variation ID: 12600 Accession: VCV000012600.14

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 534288 (GRCh38) [ NCBI UCSC ] 11: 534288 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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 24, 2015	Jul 23, 2024	Jun 3, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005343.4:c.35G>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005334.1:p.Gly12Val	missense
NM_176795.5:c.35G>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	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
NM_005343.3:c.35G>T
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

... more HGVS ... less HGVS

Protein change

G12V

Other names

p.G12V:GGC>GTA

Canonical SPDI

NC_000011.10:534287:C:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA122545 UniProtKB: P01112#VAR_006836 OMIM: 190020.0001 dbSNP: rs104894230 VarSome

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
Gene	OMIM	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.
HRAS		No evidence available	No evidence available	GRCh38 GRCh38 GRCh37	12	725
LRRC56		-	-	GRCh38 GRCh38 GRCh37	346	1059

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.
Malignant tumor of urinary bladder	Pathogenic (1)	no assertion criteria provided	Apr 1, 2012	RCV000013431.7
Costello syndrome	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Aug 21, 2023	RCV000013432.37
Myopathy, congenital, with excess of muscle spindles	Pathogenic (1)	no assertion criteria provided	Apr 1, 2012	RCV000013433.27
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 3, 2024	RCV000157912.2
Epidermal nevus	Pathogenic (1)	no assertion criteria provided	Apr 1, 2012	RCV000032850.7
Melanoma	Likely pathogenic (1)	no assertion criteria provided	Jul 14, 2015	RCV000428111.1
Thyroid tumor	Pathogenic (1)	no assertion criteria provided	Oct 2, 2014	RCV000438340.1
HRAS-related disorder	Pathogenic (1)	criteria provided, single submitter	Aug 12, 2023	RCV003415692.4
Cardiovascular phenotype	Pathogenic (1)	criteria provided, single submitter	Jul 25, 2023	RCV004018622.1

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.
Pathogenic (May 05, 2011)	criteria provided, single submitter (LMM Criteria) 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	Publications: PubMed (1) PubMed: 16170316 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 (Aug 21, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: unknown	Baylor Genetics Accession: SCV004040944.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023
Pathogenic (Jun 04, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) 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	Publications: PubMed (1) PubMed: 16170316 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 12, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	HRAS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004114489.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: The HRAS c.35G>T variant is predicted to result in the amino acid substitution p.Gly12Val. This variant has been reported as a recurrent de novo variant … (more) The HRAS c.35G>T variant is predicted to result in the amino acid substitution p.Gly12Val. This variant has been reported as a recurrent de novo variant in multiple individuals with Costello syndrome (Patient 4, Burkitt-Wright et al 2012. PubMed ID: 22495892; van der Burgt et al 2007. PubMed ID: 17412879; Bend et al. 2019. PubMed ID: 30664540; Vora et al. 2020. PubMed ID: 31974414). Of note, >90% of pathogenic HRAS variants alter the conserved glycine residues at positions 12 and 13 (Aoki et al. 2005. PubMed ID: 16170316; Gripp et al. 2006. PubMed ID: 16329078; van der Burgt et al 2007. PubMed ID: 17412879). 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)
Pathogenic (Jan 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV003825223.2 First in ClinVar: Mar 04, 2023 Last updated: Feb 04, 2024
Pathogenic (Jul 25, 2023)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV004072496.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 16170316‚ 17412879‚ 22495892 Comment: The c.35G>T (p.G12V) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to T substitution … (more) The c.35G>T (p.G12V) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to T substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed or determined to be the result of a de novo mutation in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005; van der Burgt, 2007; Burkitt-Wright, 2012). Another alteration at the same codon, c.34G>A (p.G12S), was reported in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. (less)
Pathogenic (Jun 03, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207846.12 First in ClinVar: Feb 24, 2015 Last updated: Jul 23, 2024	Comment: Published functional studies demonstrate a slower activation rate and reduced catalytic activity (PMID: 23487764, 24224811); Not observed at significant frequency in large population cohorts (gnomAD); … (more) Published functional studies demonstrate a slower activation rate and reduced catalytic activity (PMID: 23487764, 24224811); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34184824, 24224811, 22584058, 24057668, 23376849, 23093928, 22495892, 24803665, 27195699, 26325505, 28455154, 17412879, 30664540, 31974414, 29493581, 23487764) (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	Publications: PubMed (9) PubMed: 7177195‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 16170316‚ 22499344‚ 17412879‚ 8960317 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	Publications: PubMed (9) PubMed: 7177195‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 16170316‚ 22499344‚ 17412879‚ 8960317 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	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	Publications: PubMed (9) PubMed: 7177195‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 16170316‚ 22499344‚ 17412879‚ 8960317 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	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	Publications: PubMed (9) PubMed: 7177195‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 16170316‚ 22499344‚ 17412879‚ 8960317 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	Publications: PubMed (1) PubMed: 25157968 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000311189:c.35G>T
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	Publications: PubMed (4) PubMed: 19255327‚ 17384584‚ 19773371‚ 23406027 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000311189:c.35G>T
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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 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.

Comment:

The HRAS c.35G>T variant is predicted to result in the amino acid substitution p.Gly12Val. This variant has been reported as a recurrent de novo variant in multiple individuals with Costello syndrome (Patient 4, Burkitt-Wright et al 2012. PubMed ID: 22495892; van der Burgt et al 2007. PubMed ID: 17412879; Bend et al. 2019. PubMed ID: 30664540; Vora et al. 2020. PubMed ID: 31974414). Of note, >90% of pathogenic HRAS variants alter the conserved glycine residues at positions 12 and 13 (Aoki et al. 2005. PubMed ID: 16170316; Gripp et al. 2006. PubMed ID: 16329078; van der Burgt et al 2007. PubMed ID: 17412879). 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.

Comment:

The c.35G>T (p.G12V) alteration is located in exon 2 (coding exon 1) of the HRAS gene. This alteration results from a G to T substitution at nucleotide position 35, causing the glycine (G) at amino acid position 12 to be replaced by a valine (V). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been observed or determined to be the result of a de novo mutation in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005; van der Burgt, 2007; Burkitt-Wright, 2012). Another alteration at the same codon, c.34G>A (p.G12S), was reported in multiple individuals with features consistent with HRAS-related RASopathy (Aoki, 2005). This amino acid position is highly conserved in available vertebrate species. The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic.

Comment:

Published functional studies demonstrate a slower activation rate and reduced catalytic activity (PMID: 23487764, 24224811); Not observed at significant frequency in large population cohorts (gnomAD); Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34184824, 24224811, 22584058, 24057668, 23376849, 23093928, 22495892, 24803665, 27195699, 26325505, 28455154, 17412879, 30664540, 31974414, 29493581, 23487764)

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.

Comment:

Citations for germline classification of this variant

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
Neonatal lethal Costello syndrome and unusual dinucleotide deletion/insertion mutations in HRAS predicting p.Gly12Val.	Burkitt-Wright EM	American journal of medical genetics. Part A	2012	PMID: 22495892
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	-	-	-	-
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Text-mined citations for rs104894230 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_005343.4(HRAS):c.35G>T (p.Gly12Val)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894230 ...