VCV000012603.20 - ClinVar

NM_005343.4(HRAS):c.35G>C (p.Gly12Ala)

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.

(34)

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>C (p.Gly12Ala)

Variation ID: 12603 Accession: VCV000012603.20

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	Apr 4, 2013	Oct 8, 2024	Sep 24, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_005343.4:c.35G>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005334.1:p.Gly12Ala	missense
NM_176795.5:c.35G>C MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_789765.1:p.Gly12Ala	missense
NM_001130442.3:c.35G>C	NP_001123914.1:p.Gly12Ala	missense
NM_001318054.2:c.-285G>C		5 prime UTR
NM_005343.3:c.35G>C
NC_000011.10:g.534288C>G
NC_000011.9:g.534288C>G
NG_007666.1:g.6263G>C
LRG_506:g.6263G>C
LRG_506t1:c.35G>C	LRG_506p1:p.Gly12Ala
	P01112:p.Gly12Ala

... more HGVS ... less HGVS

Protein change

G12A

Other names

p.G12A:GGC>GCC

Canonical SPDI

NC_000011.10:534287:C:G

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: CA256486 UniProtKB: P01112#VAR_026106 OMIM: 190020.0004 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.
Carcinoma of esophagus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423741.2
Prostate adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433587.2
Malignant melanoma of skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000417508.2
Uterine carcinosarcoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000425511.2
Malignant neoplasm of body of uterus	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423413.2
Ovarian serous cystadenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000423622.2
Thyroid tumor	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000428172.2
Transitional cell carcinoma of the bladder	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000425989.2
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Sep 24, 2024	RCV000207503.8
Gastric adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000426130.2
Adenoid cystic carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000418547.2
Squamous cell carcinoma of the head and neck	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000432956.2
Nasopharyngeal neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000428375.2
Breast neoplasm	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000435805.2
Neoplasm of the large intestine	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000422263.2
Glioblastoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000440663.2
Hepatocellular carcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000433266.2
Acute myeloid leukemia	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000436832.2
Neoplasm of uterine cervix	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000441501.2
Costello syndrome Epidermal nevus Large congenital melanocytic nevus Linear nevus sebaceous syndrome Malignant tumor of urinary bladder Thyroid cancer, nonmedullary, 2	Pathogenic (1)	criteria provided, single submitter	Oct 31, 2018	RCV000762848.3
Multiple myeloma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000444092.2
Myelodysplastic syndrome	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000442448.2
Papillary renal cell carcinoma, sporadic	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000430806.2
Lung adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000445090.2
Squamous cell carcinoma of the skin	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000435619.2
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Mar 3, 2016	RCV000623953.4
Pancreatic adenocarcinoma	Likely pathogenic (1)	no assertion criteria provided	May 31, 2016	RCV000445257.2
Costello syndrome	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Jul 22, 2024	RCV000013437.31
Rhabdomyosarcoma	Pathogenic (1)	no assertion criteria provided	Sep 1, 2020	RCV001257536.2
Noonan syndrome and Noonan-related syndrome	Pathogenic (1)	criteria provided, single submitter	Apr 6, 2021	RCV001813186.4
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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 (Jun 04, 2014)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	none provided Affected status: yes Allele origin: unknown	Molecular Diagnostics Lab, Nemours Children's Health, Delaware Accession: SCV000263054.1 First in ClinVar: Feb 20, 2016 Last updated: Feb 20, 2016	Publications: PubMed (1) PubMed: 16170316 Number of individuals with the variant: 1 Age: 0-9 years Sex: female
Pathogenic (Apr 06, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: yes Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060961.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022
Pathogenic (Jul 17, 2017)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000698555.1 First in ClinVar: Oct 11, 2015 Last updated: Oct 11, 2015	Publications: PubMed (7) PubMed: 17979197‚ 27195699‚ 21850009‚ 16170316‚ 24224811‚ 27589201‚ 24169525 Comment: Variant summary: The HRAS c.35G>C (p.Gly12Ala) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant … (more) Variant summary: The HRAS c.35G>C (p.Gly12Ala) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that this variant increased RAS pathway activation in NIH 3T3 cells (Niihori_JHG_2011) and increased proliferation in Ba/F3 cells (Denayer_HM_2008). The variant of interest has not been found in a large, broad control population, ExAC in 120014 control chromosomes. This variant was reported in multiple Costello syndrome patients, including de novo occurrences (Aoki_NatGen_2005, Robbins_AJMG_2016, Niihori_JHG_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. (less)
Pathogenic (Sep 24, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000207845.13 First in ClinVar: Feb 24, 2015 Last updated: Oct 08, 2024	Comment: Published functional studies demonstrate a damaging effect caused by increased phosphorylation of ERK, suggesting an activation of the RAS/MAPK pathway (Denayer et al., 2008; Niihori … (more) Published functional studies demonstrate a damaging effect caused by increased phosphorylation of ERK, suggesting an activation of the RAS/MAPK pathway (Denayer et al., 2008; Niihori et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17979197, 28027064, 17601930, 30055033, 34845155, 24224811, 21686750, 22317973, 23093928, 16170316, 19035362, 24803665, 27589201, 24169525, 16835863, 30762279, 30885829, 31394527, 31560489, 33482860, 33224014, 37488489, 33057194, 35982159, 34643321, 21850009) (less)
Pathogenic (Mar 03, 2016)	criteria provided, single submitter (Ambry exome assertion method (8-5-2015)) Method: clinical testing	Inborn genetic diseases Affected status: yes Allele origin: germline	Ambry Genetics Accession: SCV000741342.3 First in ClinVar: Apr 15, 2018 Last updated: Jan 07, 2023	Publications: PubMed (6) PubMed: 23093928‚ 24803665‚ 22317973‚ 21850009‚ 21686750‚ 24224811 Number of individuals with the variant: 1 Clinical Features: Large for gestational age (present) , Overgrowth (present) , Laryngomalacia (present) , Feeding difficulties (present) , Pulmonic stenosis (disease) (present) , Coarse facial features (present) … (more) Large for gestational age (present) , Overgrowth (present) , Laryngomalacia (present) , Feeding difficulties (present) , Pulmonic stenosis (disease) (present) , Coarse facial features (present) , Macroglossia (present) , Nevus flammeus (present) , Relative macrocephaly (present) , Short palpebral fissure (present) , Wide nasal bridge (present) , Anteverted nares (present) , Preauricular pit (present) , Preauricular skin tag (present) , Prominence of the premaxilla (present) , Thick vermilion border (present) , Wide mouth (present) , Microretrognathia (present) , Umbilical hernia (present) , Hepatosplenomegaly (present) , Polyhydramnios (present) (less) Sex: female Ethnicity/Population group: Unknown
Pathogenic (Oct 31, 2018)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Malignant tumor of urinary bladder Large congenital melanocytic nevus Epidermal nevus Linear nevus sebaceous syndrome Thyroid cancer, nonmedullary, 2 Costello syndrome Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV000893208.1 First in ClinVar: Mar 31, 2019 Last updated: Mar 31, 2019	Publications: PubMed (1) PubMed: 25741868 pmc: 4544753 pmc: 4544753 DOI: 10.1038/gim.2015.30 DOI: 10.1038/gim.2015.30
Pathogenic (Apr 21, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Costello syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000956118.4 First in ClinVar: Aug 14, 2019 Last updated: Feb 20, 2024	Publications: PubMed (15) PubMed: 16170316‚ 20979192‚ 21834037‚ 21850009‚ 22317973‚ 23751039‚ 17979197‚ 24224811‚ 16372351‚ 16443854‚ 16835863‚ 17601930‚ 18042262‚ 22420426‚ 28027064 Comment: This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Ala). … (more) This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt HRAS function. ClinVar contains an entry for this variant (Variation ID: 12603). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). In at least one individual the variant was observed to be de novo. (less)
Pathogenic (Jul 22, 2024)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Costello syndrome Affected status: yes Allele origin: de novo	Clinical Genetics and Genomics, Karolinska University Hospital Accession: SCV005091973.1 First in ClinVar: Aug 04, 2024 Last updated: Aug 04, 2024	Comment: This variant was found de novo in a child with Costello syndrome. It disrupts the p.Gly12 amino acid residue in HRAS. Other variants that disrupt … (more) This variant was found de novo in a child with Costello syndrome. It disrupts the p.Gly12 amino acid residue in HRAS. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). In silico prediction indicates that this missense variant is expected to disrupt HRAS function. This missense change has been observed in individuals with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Sep 01, 2020)	no assertion criteria provided Method: provider interpretation	Rhabdomyosarcoma Affected status: yes Allele origin: germline	Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine Accession: SCV001434362.1 First in ClinVar: Oct 02, 2020 Last updated: Oct 02, 2020
Pathogenic (Oct 01, 2005)	no assertion criteria provided Method: literature only	COSTELLO SYNDROME Affected status: not provided Allele origin: germline	OMIM Accession: SCV000033684.1 First in ClinVar: Apr 04, 2013 Last updated: Apr 04, 2013	Publications: PubMed (1) PubMed: 16170316 Comment on evidence: In 1 Japanese and 1 Italian patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35G-C transversion in the HRAS gene that … (more) In 1 Japanese and 1 Italian patient with Costello syndrome (218040), Aoki et al. (2005) found a germline 35G-C transversion in the HRAS gene that caused a gly12-to-ala (G12A) amino acid substitution. (less)
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Carcinoma of esophagus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506520.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Prostate adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506521.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Pancreatic adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506522.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Gastric adenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506523.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Acute myeloid leukemia (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506524.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Multiple myeloma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506525.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Transitional cell carcinoma of the bladder (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506526.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Breast neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506527.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Adenoid cystic carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506528.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Nasopharyngeal neoplasm (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506529.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Squamous cell carcinoma of the skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506530.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant melanoma of skin (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506531.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Thyroid tumor (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506532.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of uterine cervix (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506533.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Ovarian serous cystadenocarcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506534.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Papillary renal cell carcinoma, sporadic (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506535.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Glioblastoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506536.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Malignant neoplasm of body of uterus (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506537.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Hepatocellular carcinoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506538.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Myelodysplastic syndrome (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506539.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Neoplasm of the large intestine (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506540.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506541.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	None (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506542.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
Likely pathogenic (May 31, 2016)	no assertion criteria provided Method: literature only	Uterine carcinosarcoma (Somatic mutation) Affected status: yes Allele origin: somatic	Database of Curated Mutations (DoCM) Accession: SCV000506543.1 First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017	Publications: PubMed (1) PubMed: 26619011 Other databases http://docm.genome.wustl.edu/var… http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C
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Comment:

Variant summary: The HRAS c.35G>C (p.Gly12Ala) variant involves the alteration of a conserved nucleotide. 3/3 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). Functional studies showed that this variant increased RAS pathway activation in NIH 3T3 cells (Niihori_JHG_2011) and increased proliferation in Ba/F3 cells (Denayer_HM_2008). The variant of interest has not been found in a large, broad control population, ExAC in 120014 control chromosomes. This variant was reported in multiple Costello syndrome patients, including de novo occurrences (Aoki_NatGen_2005, Robbins_AJMG_2016, Niihori_JHG_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

Comment:

Published functional studies demonstrate a damaging effect caused by increased phosphorylation of ERK, suggesting an activation of the RAS/MAPK pathway (Denayer et al., 2008; Niihori et al., 2011); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Missense variants in this gene are a common cause of disease and they are underrepresented in the general population; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17979197, 28027064, 17601930, 30055033, 34845155, 24224811, 21686750, 22317973, 23093928, 16170316, 19035362, 24803665, 27589201, 24169525, 16835863, 30762279, 30885829, 31394527, 31560489, 33482860, 33224014, 37488489, 33057194, 35982159, 34643321, 21850009)

Comment:

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 12 of the HRAS protein (p.Gly12Ala). This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) indicates that this missense variant is expected to disrupt HRAS function. ClinVar contains an entry for this variant (Variation ID: 12603). This missense change has been observed in individual(s) with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). In at least one individual the variant was observed to be de novo.

Comment:

This variant was found de novo in a child with Costello syndrome. It disrupts the p.Gly12 amino acid residue in HRAS. Other variants that disrupt this residue have been determined to be pathogenic (PMID: 16170316, 20979192, 21834037, 21850009, 22317973, 23751039). Experimental studies have shown that this missense change affects HRAS function (PMID: 17979197, 21850009, 24224811). In silico prediction indicates that this missense variant is expected to disrupt HRAS function. This missense change has been observed in individuals with Costello syndrome (PMID: 16170316, 16372351, 16443854, 16835863, 17601930, 18042262, 21850009, 22420426, 28027064). For these reasons, this variant has been classified as Pathogenic.

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
Germline Cancer Predisposition Variants in Pediatric Rhabdomyosarcoma: A Report From the Children's Oncology Group.	Li H	Journal of the National Cancer Institute	2021	PMID: 33372952
Novel pathogenic variant in the HRAS gene with lethal outcome and a broad phenotypic spectrum among Polish patients with Costello syndrome.	Pelc M	Clinical dysmorphology	2017	PMID: 28027064
Paternal uniparental disomy with segmental loss of heterozygosity of chromosome 11 are hallmark characteristics of syndromic and sporadic embryonal rhabdomyosarcoma.	Robbins KM	American journal of medical genetics. Part A	2016	PMID: 27589201
The Splicing Efficiency of Activating HRAS Mutations Can Determine Costello Syndrome Phenotype and Frequency in Cancer.	Hartung AM	PLoS genetics	2016	PMID: 27195699
Identifying recurrent mutations in cancer reveals widespread lineage diversity and mutational specificity.	Chang MT	Nature biotechnology	2016	PMID: 26619011
Structure-energy-based predictions and network modelling of RASopathy and cancer missense mutations.	Kiel C	Molecular systems biology	2014	PMID: 24803665
HRAS mutations in bladder cancer at an early age and the possible association with the Costello Syndrome.	Beukers W	European journal of human genetics : EJHG	2014	PMID: 24169525
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
Clinical and molecular analysis of RASopathies in a group of Turkish patients.	Şimşek-Kiper PÖ	Clinical genetics	2013	PMID: 22420426
A structural systems biology approach for quantifying the systemic consequences of missense mutations in proteins.	Cheng TM	PLoS computational biology	2012	PMID: 23093928
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
De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features.	Søvik O	BMJ case reports	2009	PMID: 21686750
Mutation and phenotypic spectrum in patients with cardio-facio-cutaneous and Costello syndrome.	Schulz AL	Clinical genetics	2008	PMID: 18042262
Mutation analysis in Costello syndrome: functional and structural characterization of the HRAS p.Lys117Arg mutation.	Denayer E	Human mutation	2008	PMID: 17979197
De novo HRAS and KRAS mutations in two siblings with short stature and neuro-cardio-facio-cutaneous features.	Søvik O	Journal of medical genetics	2007	PMID: 17601930
Paternal bias in parental origin of HRAS mutations in Costello syndrome.	Sol-Church K	Human mutation	2006	PMID: 16835863
Genotype-phenotype correlation in Costello syndrome: HRAS mutation analysis in 43 cases.	Kerr B	Journal of medical genetics	2006	PMID: 16443854
HRAS mutations in Costello syndrome: detection of constitutional activating mutations in codon 12 and 13 and loss of wild-type allele in malignancy.	Estep AL	American journal of medical genetics. Part A	2006	PMID: 16372351
Germline mutations in HRAS proto-oncogene cause Costello syndrome.	Aoki Y	Nature genetics	2005	PMID: 16170316
http://docm.genome.wustl.edu/variants/ENST00000397594:c.35G>C	-	-	-	-
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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 Oct 08, 2024

ClinVar Genomic variation as it relates to human health

NM_005343.4(HRAS):c.35G>C (p.Gly12Ala)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs104894230 ...