VCV000180718.20 - ClinVar

NM_002880.4(RAF1):c.1113T>C (p.Asp371=)

Germline

Top reviewed classifications are shown here.

Submission summary:

6 submissions

6 submitters

4 conditions

Reviewed by expert panel

Likely benign

Mar 2020 by ClinGen RASopa… FDA Recognized Database

for RASopathy

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002880.4(RAF1):c.1113T>C (p.Asp371=)

Variation ID: 180718 Accession: VCV000180718.20

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.2 3: 12591788 (GRCh38) [ NCBI UCSC ] 3: 12633287 (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	May 1, 2024	Mar 9, 2020

HGVS

Nucleotide	Protein	Molecular consequence
NM_002880.4:c.1113T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002871.1:p.Asp371=	synonymous
NM_001354689.3:c.1173T>C	NP_001341618.1:p.Asp391=	synonymous
NM_001354690.3:c.1113T>C	NP_001341619.1:p.Asp371=	synonymous
NM_001354691.3:c.870T>C	NP_001341620.1:p.Asp290=	synonymous
NM_001354692.3:c.870T>C	NP_001341621.1:p.Asp290=	synonymous
NM_001354693.3:c.1014T>C	NP_001341622.1:p.Asp338=	synonymous
NM_001354694.3:c.930T>C	NP_001341623.1:p.Asp310=	synonymous
NM_001354695.3:c.771T>C	NP_001341624.1:p.Asp257=	synonymous
NM_002880.3(RAF1):c.1113T>C
NR_148940.3:n.1557T>C		non-coding transcript variant
NR_148941.3:n.1503T>C		non-coding transcript variant
NR_148942.3:n.1442T>C		non-coding transcript variant
NC_000003.12:g.12591788A>G
NC_000003.11:g.12633287A>G
NG_007467.1:g.77392T>C
LRG_413:g.77392T>C
LRG_413t1:c.1113T>C	LRG_413p1:p.Asp371=
LRG_413t2:c.1173T>C	LRG_413p2:p.Asp391=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000003.12:12591787:A: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.

The Genome Aggregation Database (gnomAD) 0.00002

Trans-Omics for Precision Medicine (TOPMed) 0.00002

The Genome Aggregation Database (gnomAD), exomes 0.00003

Exome Aggregation Consortium (ExAC) 0.00004

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00015

Links

ClinGen: CA235339 dbSNP: rs146668293 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.
RAF1		No evidence available	No evidence available	GRCh38 GRCh37	1090	1145

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 provided	Likely benign (2)	criteria provided, single submitter	Jul 10, 2019	RCV000157688.14
Cardiovascular phenotype	Likely benign (1)	criteria provided, single submitter	Oct 24, 2017	RCV000618075.11
RASopathy	Likely benign (2)	reviewed by expert panel	Mar 9, 2020	RCV001084681.17
Dilated cardiomyopathy 1NN LEOPARD syndrome 2 Noonan syndrome 5	Likely benign (1)	criteria provided, single submitter	Jul 26, 2021	RCV002505186.8

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.
Likely benign (Mar 09, 2020)	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1) Method: curation	RASopathy (Autosomal dominant inheritance) Affected status: unknown Allele origin: germline	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV001335318.1 First in ClinVar: Jun 12, 2020 Last updated: Jun 12, 2020	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ca1f922a-c651-4ca4-8afe-a28dde261256 Comment: The c.1113T>C (p.Asp371=) is present in 7/1113684 European alleles (MAF 2.88e-05, 95% CI) gnomAD v2.1.1. Sixteen apparently unaffected parental samples involved in whole exome testing … (more) The c.1113T>C (p.Asp371=) is present in 7/1113684 European alleles (MAF 2.88e-05, 95% CI) gnomAD v2.1.1. Sixteen apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time (BS2 not met; SCV000515669.4). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Computational prediction tools and conservation analysis suggest that the p.Asp371= variant does not impact the protein (BP4). In summary, the clinical significance of the p.Asp371= variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP7, BP4. (less)
Likely benign (Jul 26, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Noonan syndrome 5 LEOPARD syndrome 2 Dilated cardiomyopathy 1NN Affected status: unknown Allele origin: unknown	Fulgent Genetics, Fulgent Genetics Accession: SCV002805470.1 First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022
Likely benign (Jul 10, 2019)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000515669.6 First in ClinVar: Mar 08, 2017 Last updated: Mar 04, 2023
Likely benign (Nov 27, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	RASopathy Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001010386.6 First in ClinVar: Dec 17, 2019 Last updated: Feb 14, 2024
Likely benign (Oct 24, 2017)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000736067.5 First in ClinVar: Apr 14, 2018 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)
Uncertain significance (Jan 15, 2015)	no assertion criteria provided Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center Accession: SCV000207672.1 First in ClinVar: Feb 24, 2015 Last updated: Feb 24, 2015

Comment:

The c.1113T>C (p.Asp371=) is present in 7/1113684 European alleles (MAF 2.88e-05, 95% CI) gnomAD v2.1.1. Sixteen apparently unaffected parental samples involved in whole exome testing were observed with this variant supporting that this variant is likely benign; however, this evidence does not meet current scoring criteria for BS2 at this time (BS2 not met; SCV000515669.4). This variant is a synonymous (silent) variant at a nucleotide that is not highly conserved and is not predicted to impact splicing (BP7). Computational prediction tools and conservation analysis suggest that the p.Asp371= variant does not impact the protein (BP4). In summary, the clinical significance of the p.Asp371= variant is likely benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP7, BP4.

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
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/ca1f922a-c651-4ca4-8afe-a28dde261256	-	-	-	-

Text-mined citations for rs146668293 ...

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 10, 2024

ClinVar Genomic variation as it relates to human health

NM_002880.4(RAF1):c.1113T>C (p.Asp371=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs146668293 ...