VCV000040441.42 - ClinVar

NM_005343.4(HRAS):c.357C>T (p.Asp119=)

Germline

Top reviewed classifications are shown here.

Submission summary:

14 submissions

14 submitters

9 conditions

Reviewed by expert panel

Benign

Apr 2017 by ClinGen RASopa… FDA Recognized Database

for Noonan syndrome and Noonan-related syndrome

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_005343.4(HRAS):c.357C>T (p.Asp119=)

Variation ID: 40441 Accession: VCV000040441.42

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 11p15.5 11: 533546 (GRCh38) [ NCBI UCSC ] 11: 533546 (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	Jan 31, 2015	Oct 20, 2024	Apr 18, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_005343.4:c.357C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_005334.1:p.Asp119=	synonymous
NM_176795.5:c.357C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_789765.1:p.Asp119=	synonymous
NM_001130442.3:c.357C>T	NP_001123914.1:p.Asp119=	synonymous
NM_001318054.1:c.38C>T
NM_001318054.2:c.38C>T	NP_001304983.1:p.Thr13Ile	missense
NC_000011.10:g.533546G>A
NC_000011.9:g.533546G>A
NG_007666.1:g.7005C>T
LRG_506:g.7005C>T
LRG_506t1:c.357C>T	LRG_506p1:p.Asp119=

... more HGVS ... less HGVS

Protein change

T13I

Other names

p.D119D
NM_005343.3(HRAS):c.357C>T
p.Asp119Asp

Canonical SPDI

NC_000011.10:533545:G: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.

0.00080 (A)

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

1000 Genomes Project 0.00080

Exome Aggregation Consortium (ExAC) 0.00095

1000 Genomes Project 30x 0.00078

The Genome Aggregation Database (gnomAD), exomes 0.00105

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00108

Trans-Omics for Precision Medicine (TOPMed) 0.00108

The Genome Aggregation Database (gnomAD) 0.00121

Links

dbSNP: rs111352454 ClinGen: CA135978 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.
not specified	Benign (3)	criteria provided, multiple submitters, no conflicts	Dec 16, 2016	RCV000038458.10
Costello syndrome	Benign (1)	criteria provided, single submitter	Jan 29, 2024	RCV000227939.13
RASopathy	Benign (1)	reviewed by expert panel	Apr 18, 2017	RCV000522686.2
Costello syndrome Epidermal nevus Large congenital melanocytic nevus Linear nevus sebaceous syndrome Malignant tumor of urinary bladder Thyroid cancer, nonmedullary, 2	Likely benign (1)	criteria provided, single submitter	Jul 26, 2021	RCV002477043.1
Hereditary cancer-predisposing syndrome	Benign (1)	criteria provided, single submitter	Feb 24, 2020	RCV002257371.1
Noonan syndrome and Noonan-related syndrome	Benign (1)	criteria provided, single submitter	Jul 1, 2020	RCV001813236.3
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Nov 19, 2019	RCV002453280.2
HRAS-related disorder	Benign (1)	no assertion criteria provided	Oct 1, 2019	RCV003924885.2
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV001711139.15

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.
Benign (Apr 18, 2017)	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1) Method: curation	Noonan syndrome and Noonan-related syndrome (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616471.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4da936bb-53cd-4fad-8d47-40c90dc60a73 Comment: The filtering allele frequency of the c.357C>T (p.Asp119=) variant in the HRAS gene is 0.129% (102/66416) of European chromosomes by the Exome Aggregation Consortium, which … (more) The filtering allele frequency of the c.357C>T (p.Asp119=) variant in the HRAS gene is 0.129% (102/66416) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581) (less)
Benign (Aug 18, 2011)	criteria provided, single submitter (LMM Criteria) Method: clinical testing	not specified Affected status: not provided Allele origin: germline	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000062134.5 First in ClinVar: May 03, 2013 Last updated: Jan 31, 2015	Comment: Asp119Asp in exon 4 of HRAS: This variant is not expected to have clinical signi ficance because it has been identified in 8/214(3.7%) chromosomes (rs111352454). … (more) Asp119Asp in exon 4 of HRAS: This variant is not expected to have clinical signi ficance because it has been identified in 8/214(3.7%) chromosomes (rs111352454). In addition, this variant does not alter an amino acid residue and is not loca ted near a splice junction. Furthermore, this variant has previously been identi fied in our laboratory in an individual with a de novo variant in BRAF and in an unaffected parent of that individual. (less) Number of individuals with the variant: 13
Likely benign (Jul 26, 2021)	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: SCV002798843.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Benign (Jan 29, 2024)	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: SCV000288857.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 14, 2024
Benign (Jul 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004134985.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: HRAS: BP4, BP7, BS1, BS2 Number of individuals with the variant: 12
Benign (Dec 16, 2016)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not specified Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000703503.2 First in ClinVar: Jan 31, 2015 Last updated: Jan 31, 2015	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HRAS Number of individuals with the variant: 1 Sex: mixed
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001942933.2 First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023
Benign (Jul 01, 2020)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome and Noonan-related syndrome Affected status: unknown Allele origin: germline	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060513.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022
Likely benign (Nov 19, 2019)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV002614122.2 First in ClinVar: Nov 29, 2022 Last updated: May 01, 2024	Comment: This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of … (more) This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Benign (Feb 24, 2020)	criteria provided, single submitter (Sema4 Curation Guidelines) Method: curation	Hereditary cancer-predisposing syndrome Affected status: unknown Allele origin: germline	Sema4, Sema4 Accession: SCV002537976.1 First in ClinVar: Jun 24, 2022 Last updated: Jun 24, 2022
Benign (Oct 01, 2019)	no assertion criteria provided Method: clinical testing	HRAS-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004745783.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 2024	Comment: This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001956314.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001924427.1 First in ClinVar: Sep 24, 2021 Last updated: Sep 24, 2021
Likely benign (-)	no assertion criteria provided Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001963803.1 First in ClinVar: Oct 07, 2021 Last updated: Oct 07, 2021
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Comment:

The filtering allele frequency of the c.357C>T (p.Asp119=) variant in the HRAS gene is 0.129% (102/66416) of European chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)

Comment:

Asp119Asp in exon 4 of HRAS: This variant is not expected to have clinical signi ficance because it has been identified in 8/214(3.7%) chromosomes (rs111352454). In addition, this variant does not alter an amino acid residue and is not loca ted near a splice junction. Furthermore, this variant has previously been identi fied in our laboratory in an individual with a de novo variant in BRAF and in an unaffected parent of that individual.

Comment:

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.

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
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=HRAS	-	-	-	-
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/4da936bb-53cd-4fad-8d47-40c90dc60a73	-	-	-	-

Text-mined citations for rs111352454 ...

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 20, 2024

ClinVar Genomic variation as it relates to human health

NM_005343.4(HRAS):c.357C>T (p.Asp119=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs111352454 ...