VCV000012600.18 - ClinVar

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

Germline

Classification

criteria provided, multiple submitters, no conflicts. Learn more about how ClinVar calculates review status.

Pathogenic

7 out of 11 submissions contributed to this 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.

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: VCV000012600.18

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	Sep 6, 2025	Aug 29, 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

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	11	765
LRRC56		-	-	GRCh38 GRCh38 GRCh37	438	1193

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 29, 2024	RCV000013432.43
Myopathy, congenital, with excess of muscle spindles	Pathogenic (1)	no assertion criteria provided	Apr 1, 2012	RCV000013433.27
Epidermal nevus	Pathogenic (1)	no assertion criteria provided	Apr 1, 2012	RCV000032850.7
not provided	Pathogenic (1)	criteria provided, single submitter	Jun 3, 2024	RCV000157912.2
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.	Expand all rows Collapse all rows 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) C Contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	Costello syndrome	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: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: not provided more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: not provided Number of individuals with the variant: 1

Pathogenic (Aug 12, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	HRAS-related condition	PreventionGenetics, part of Exact Sciences Accession: SCV004114489.1 First in ClinVar: Nov 20, 2023 Last updated: Nov 20, 2023	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Aug 21, 2023) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Costello syndrome	Baylor Genetics Accession: SCV004040944.1 First in ClinVar: Oct 07, 2023 Last updated: Oct 07, 2023	Observation: 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: unknown Affected status: unknown

Pathogenic (Jul 25, 2023) C Contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV004072496.2 First in ClinVar: Oct 28, 2023 Last updated: May 01, 2024	Publications: PubMed (3) PubMed: 16170316‚ 17412879‚ 22495892 Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jun 03, 2024) C Contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	not provided	GeneDx Accession: SCV000207846.12 First in ClinVar: Feb 24, 2015 Last updated: Jul 23, 2024	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Pathogenic (Aug 29, 2024) C Contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Costello syndrome	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV005835934.1 First in ClinVar: Feb 25, 2025 Last updated: Feb 25, 2025	Publications: PubMed (7) PubMed: 16170316‚ 20979192‚ 21834037‚ 21850009‚ 22317973‚ 23751039‚ 24224811 Comment: show This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12600). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 24224811). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Jan 07, 2022) C Contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Costello syndrome	Revvity Omics, Revvity Accession: SCV003825223.3 First in ClinVar: Mar 04, 2023 Last updated: Sep 06, 2025	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Pathogenic (Apr 01, 2012) N Not contributing to aggregate classification	no assertion criteria provided	BLADDER CANCER, SOMATIC	OMIM Accession: SCV000033678.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 17412879‚ 22499344‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 7177195‚ 8960317 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided 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) N Not contributing to aggregate classification	no assertion criteria provided	COSTELLO SYNDROME	OMIM Accession: SCV000033679.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 17412879‚ 22499344‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 7177195‚ 8960317 Observation: 1 Collection method: literature only Allele origin: unknown Affected status: not provided more Observation 1 Collection method: literature only Allele origin: unknown Affected status: not provided 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) N Not contributing to aggregate classification	no assertion criteria provided	MYOPATHY, CONGENITAL, WITH EXCESS OF MUSCLE SPINDLES	OMIM Accession: SCV000033680.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 17412879‚ 22499344‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 7177195‚ 8960317 Observation: 1 Collection method: literature only Allele origin: unknown Affected status: not provided more Observation 1 Collection method: literature only Allele origin: unknown Affected status: not provided 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) N Not contributing to aggregate classification	no assertion criteria provided	EPIDERMAL NEVUS, SOMATIC	OMIM Accession: SCV000056619.4 First in ClinVar: Apr 04, 2013 Last updated: Dec 15, 2018	Publications: PubMed (9) PubMed: 16170316‚ 17412879‚ 22499344‚ 2999610‚ 3537694‚ 6092966‚ 6330729‚ 7177195‚ 8960317 Observation: 1 Collection method: literature only Allele origin: somatic Affected status: not provided more Observation 1 Collection method: literature only Allele origin: somatic Affected status: not provided 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)

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)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12600). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt HRAS protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects HRAS function (PMID: 24224811). This variant disrupts the p.Gly12 amino acid residue in HRAS. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Kinetic mechanisms of mutation-dependent Harvey Ras activation and their relevance for the development of Costello syndrome.	Wey M	Biochemistry	2013	PMID: 24224811
Craniofacial and dental malformations in Costello syndrome: A detailed evaluation using multi-detector row computed tomography.	Takahashi M	Congenital anomalies	2013	PMID: 23751039
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
C4ST-1/CHST11-controlled chondroitin sulfation interferes with oncogenic HRAS signaling in Costello syndrome.	Klüppel M	European journal of human genetics : EJHG	2012	PMID: 22317973
HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.	Niihori T	Journal of human genetics	2011	PMID: 21850009
Molecular confirmation of HRAS p.G12S in siblings with Costello syndrome.	Gripp KW	American journal of medical genetics. Part A	2011	PMID: 21834037
Costello syndrome with severe cutis laxa and mosaic HRAS G12S mutation.	Girisha KM	American journal of medical genetics. Part A	2010	PMID: 20979192
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
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
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Text-mined citations for rs104894230 ...

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Record last updated Feb 08, 2026