VCV000044623.47 - ClinVar

NM_002880.4(RAF1):c.1941C>T (p.Val647=)

Germline

Top reviewed classifications are shown here.

Submission summary:

14 submissions

13 submitters

7 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_002880.4(RAF1):c.1941C>T (p.Val647=)

Variation ID: 44623 Accession: VCV000044623.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.2 3: 12584520 (GRCh38) [ NCBI UCSC ] 3: 12626019 (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 17, 2015	Oct 20, 2024	Apr 18, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_002880.4:c.1941C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002871.1:p.Val647=	synonymous
NM_001354689.3:c.2001C>T	NP_001341618.1:p.Val667=	synonymous
NM_001354690.3:c.1941C>T	NP_001341619.1:p.Val647=	synonymous
NM_001354691.3:c.1698C>T	NP_001341620.1:p.Val566=	synonymous
NM_001354692.3:c.1698C>T	NP_001341621.1:p.Val566=	synonymous
NM_001354693.3:c.1842C>T	NP_001341622.1:p.Val614=	synonymous
NM_001354694.3:c.1758C>T	NP_001341623.1:p.Val586=	synonymous
NM_001354695.3:c.1599C>T	NP_001341624.1:p.Val533=	synonymous
NR_148940.3:n.2385C>T		non-coding transcript variant
NR_148941.3:n.2331C>T		non-coding transcript variant
NR_148942.3:n.2270C>T		non-coding transcript variant
NC_000003.12:g.12584520G>A
NC_000003.11:g.12626019G>A
NG_007467.1:g.84660C>T
LRG_413:g.84660C>T
LRG_413t1:c.1941C>T	LRG_413p1:p.Val647=
LRG_413t2:c.2001C>T	LRG_413p2:p.Val667=

... more HGVS ... less HGVS

Protein change

Other names

p.V647V:GTC>GTT
NM_002880.3(RAF1):c.1941C>T

Canonical SPDI

NC_000003.12:12584519: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.

0.00439 (A)

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

1000 Genomes Project 0.00439

1000 Genomes Project 30x 0.00468

Trans-Omics for Precision Medicine (TOPMed) 0.00652

The Genome Aggregation Database (gnomAD), exomes 0.00679

Exome Aggregation Consortium (ExAC) 0.00708

The Genome Aggregation Database (gnomAD) 0.00729

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00830

Links

ClinGen: CA134718 dbSNP: rs3730297 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
MKRN2		-	-	GRCh38 GRCh37	31	65

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	Jan 12, 2012	RCV000037685.18
RASopathy	Benign (3)	reviewed by expert panel	Apr 18, 2017	RCV000149840.26
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Dec 8, 2014	RCV000252430.11
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	Jul 1, 2024	RCV000857577.29
Noonan syndrome 5	Likely benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV001143979.12
LEOPARD syndrome 2	Benign (1)	criteria provided, single submitter	Jan 12, 2018	RCV001145869.12
Noonan syndrome and Noonan-related syndrome	Benign (1)	criteria provided, single submitter	Jul 8, 2021	RCV001813331.11

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: SCV000616477.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/62438d26-e85a-41a6-ae0f-89550c868512 Comment: The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) of European chromosomes by the Exome Aggregation Consortium, which … (more) The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) 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 (Jul 08, 2021)	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: SCV002060609.1 First in ClinVar: Jan 22, 2022 Last updated: Jan 22, 2022
Benign (Nov 09, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001472278.3 First in ClinVar: Jan 26, 2021 Last updated: Feb 20, 2024
Benign (Dec 08, 2014)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318679.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as 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 (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	NOT SPECIFIED Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV000309261.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016
Benign (Jan 12, 2012)	criteria provided, single submitter (GeneDx Variant Classification (06012015)) Method: clinical testing	not specified Affected status: yes Allele origin: germline	GeneDx Accession: SCV000171286.11 First in ClinVar: Jun 23, 2014 Last updated: Oct 02, 2016	Comment: This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more) This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
Benign (May 11, 2009)	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: SCV000061347.6 First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016	Number of individuals with the variant: 68
Likely benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	Noonan syndrome 5 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001304553.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. (less)
Benign (Jan 12, 2018)	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019) Method: clinical testing	LEOPARD syndrome 2 Affected status: unknown Allele origin: germline	Illumina Laboratory Services, Illumina Accession: SCV001306573.1 First in ClinVar: May 31, 2020 Last updated: May 31, 2020	Comment: This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more) This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
Benign (Feb 01, 2024)	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: SCV000287741.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005239358.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 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: SCV003916410.13 First in ClinVar: Apr 23, 2023 Last updated: Oct 20, 2024	Comment: MKRN2: BS1, BS2; RAF1: BP4, BS1, BS2 Number of individuals with the variant: 21
Benign (-)	no assertion criteria provided Method: clinical testing	Rasopathy Affected status: yes Allele origin: unknown	Baylor Genetics Accession: SCV000196684.1 First in ClinVar: Jan 17, 2015 Last updated: Jan 17, 2015	Comment: Variant classified using ACMG guidelines
not provided (-)	no classification provided Method: phenotyping only	Not Provided Affected status: unknown Allele origin: unknown	GenomeConnect - CFC International Accession: SCV001156335.1 First in ClinVar: Feb 06, 2020 Last updated: Feb 06, 2020	Comment: Variant interpreted as Benign and reported on 04-30-2009 by Lab or GTR ID 239772. GenomeConnect-CFC International assertions are reported exactly as they appear on the … (more) Variant interpreted as Benign and reported on 04-30-2009 by Lab or GTR ID 239772. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. (less) Clinical Features: Abnormality of eye movement (present) , Hypermetropia (present) , Myopia (present) , Ptosis (present) , Abnormal facial shape (present) , Abnormality of the oral cavity … (more) Abnormality of eye movement (present) , Hypermetropia (present) , Myopia (present) , Ptosis (present) , Abnormal facial shape (present) , Abnormality of the oral cavity (present) , Abnormality of the neck (present) , Abnormality of the nose (present) , Feeding difficulties (present) , Abnormality of the intestine (present) , Abnormality of the large intestine (present) , Abnormality of the stomach (present) , Abnormality of the bladder (present) , Abnormal renal physiology (present) , Abnormal renal morphology (present) , Abnormality of the male genitalia (present) , Abnormality of the urethra (present) , Abnormality of the ureter (present) , Abnormality of the curvature of the vertebral column (present) , Joint hypermobility (present) , Abnormality of the musculature of the limbs (present) , Abnormality of the musculature of the pelvis (present) , Abnormality of muscle morphology (present) , Abnormality of muscle physiology (present) , Morphological abnormality of the central nervous system (present) , Cerebral palsy (present) , Cognitive impairment (present) , Generalized hypotonia (present) , Seizures (present) , Abnormality of the amniotic fluid (present) , Abnormal delivery (present) , Premature birth (present) , Autistic behavior (present) (less) Indication for testing: Diagnostic Age: 0-9 years Sex: male Testing laboratory: PreventionGenetics,PreventionGenetics Date variant was reported to submitter: 2009-04-30 Testing laboratory interpretation: Benign
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Comment:

The filtering allele frequency of the c.1941C>T (p.Val647=) variant in the RAF1 gene is 1.04% (738/66732) 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:

This alteration is classified as 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.

Comment:

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.

Comment:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Variant interpreted as Benign and reported on 04-30-2009 by Lab or GTR ID 239772. GenomeConnect-CFC International assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant.

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:

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/62438d26-e85a-41a6-ae0f-89550c868512	-	-	-	-

Text-mined citations for rs3730297 ...

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

Record last updated Nov 25, 2024

ClinVar Genomic variation as it relates to human health

NM_002880.4(RAF1):c.1941C>T (p.Val647=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs3730297 ...