VCV000040628.47 - ClinVar

NM_002880.4(RAF1):c.1914G>A (p.Thr638=)

Germline

Reviewed by expert panel

Reviewed by expert panel. Learn more about how ClinVar calculates review status.

Benign

for Noonan syndrome and Noonan-related syndrome

Classification is based on the expert panel submission

Apr 2017 by ClinGen RASopathy Variant Curation Expert Panel

The classification is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

FDA Recognized Database

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002880.4(RAF1):c.1914G>A (p.Thr638=)

Variation ID: 40628 Accession: VCV000040628.47

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 3p25.2 3: 12584547 (GRCh38) [ NCBI UCSC ] 3: 12626046 (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	Oct 2, 2016	Oct 25, 2025	Apr 18, 2017

HGVS

Nucleotide	Protein	Molecular consequence
NM_002880.4:c.1914G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002871.1:p.Thr638=	synonymous
NM_001354689.3:c.1974G>A	NP_001341618.1:p.Thr658=	synonymous
NM_001354690.3:c.1914G>A	NP_001341619.1:p.Thr638=	synonymous
NM_001354691.3:c.1671G>A	NP_001341620.1:p.Thr557=	synonymous
NM_001354692.3:c.1671G>A	NP_001341621.1:p.Thr557=	synonymous
NM_001354693.3:c.1815G>A	NP_001341622.1:p.Thr605=	synonymous
NM_001354694.3:c.1731G>A	NP_001341623.1:p.Thr577=	synonymous
NM_001354695.3:c.1572G>A	NP_001341624.1:p.Thr524=	synonymous
NR_148940.3:n.2358G>A		non-coding transcript variant
NR_148941.3:n.2304G>A		non-coding transcript variant
NR_148942.3:n.2243G>A		non-coding transcript variant
NC_000003.12:g.12584547C>T
NC_000003.11:g.12626046C>T
NG_007467.1:g.84633G>A
LRG_413:g.84633G>A
LRG_413t1:c.1914G>A	LRG_413p1:p.Thr638=
LRG_413t2:c.1974G>A	LRG_413p2:p.Thr658=

... more HGVS ... less HGVS

Protein change

Other names

p.T638T
NM_002880.3(RAF1):c.1914G>A

Canonical SPDI

NC_000003.12:12584546:C:T

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.

0.00359 (T)

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

The Genome Aggregation Database (gnomAD), exomes 0.00065

1000 Genomes Project 30x 0.00312

1000 Genomes Project 0.00359

Trans-Omics for Precision Medicine (TOPMed) 0.00008

The Genome Aggregation Database (gnomAD) 0.00001

The Genome Aggregation Database (gnomAD) 0.00034

Links

ClinGen: CA134715 dbSNP: rs144876026 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	1271	1326

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	Aug 30, 2019	RCV000037684.13
Noonan syndrome 5	Likely benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000279428.6
LEOPARD syndrome 2	Benign (1)	criteria provided, single submitter	Jan 13, 2018	RCV000402345.6
RASopathy	Benign (2)	reviewed by expert panel	Apr 18, 2017	RCV000519653.14
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	May 21, 2015	RCV000242024.4
not provided	Benign (2)	criteria provided, multiple submitters, no conflicts	Apr 1, 2023	RCV001705628.19
Noonan syndrome and Noonan-related syndrome	Benign (1)	criteria provided, single submitter	Apr 9, 2021	RCV001813274.3

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.
Benign (Apr 18, 2017) C Contributing to aggregate classification	reviewed by expert panel (ClinGen RASopathy ACMG Specifications v1)	Noonan syndrome and Noonan-related syndrome (Autosomal dominant inheritance)	ClinGen RASopathy Variant Curation Expert Panel FDA Recognized Database Accession: SCV000616478.4 First in ClinVar: Dec 19, 2017 Last updated: Dec 11, 2022	Other databases https://erepo.clinicalgenome.org… https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5dd1c397-b2a2-4954-bbbb-583d4a4576dc Comment: show The filtering allele frequency of the c.1914G>A (p.Thr638=) variant in the RAF1 gene is 0.926% (174/16512) of South Asian 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) Observation: 1 Collection method: curation Allele origin: germline Affected status: unknown Observation 1 Collection method: curation Allele origin: germline Affected status: unknown

Benign (-) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	NOT SPECIFIED	PreventionGenetics, part of Exact Sciences Accession: SCV000309260.1 First in ClinVar: Oct 02, 2016 Last updated: Oct 02, 2016	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jan 13, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	LEOPARD syndrome 2	Illumina Laboratory Services, Illumina Accession: SCV000440615.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Likely benign (Jan 13, 2018) N Not contributing to aggregate classification	criteria provided, single submitter (ICSL Variant Classification Criteria 13 December 2019)	Noonan syndrome 5	Illumina Laboratory Services, Illumina Accession: SCV000440616.3 First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Mar 03, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (GeneDx Variant Classification Process June 2021)	Not Provided	GeneDx Accession: SCV001915674.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes

Benign (Aug 10, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (LMM Criteria)	not specified	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine Accession: SCV000061346.6 First in ClinVar: May 03, 2013 Last updated: Oct 02, 2016	Comment: show p.Thr638Thr in exon 17 of RAF1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 1% (174/16512) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org/; dbSNP rs144876026). (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: 5

Benign (Aug 30, 2019) N Not contributing to aggregate classification	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	not specified	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV001360610.1 First in ClinVar: Jun 22, 2020 Last updated: Jun 22, 2020	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Apr 09, 2021) N Not contributing to aggregate classification	criteria provided, single submitter (ACMG Guidelines, 2015)	Noonan syndrome and Noonan-related syndrome	Genome Diagnostics Laboratory, The Hospital for Sick Children Accession: SCV002060608.1 First in ClinVar: Jan 20, 2022 Last updated: Jan 20, 2022	Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (May 21, 2015) N Not contributing to aggregate classification	criteria provided, single submitter (Ambry Variant Classification Scheme 2023)	Cardiovascular phenotype	Ambry Genetics Accession: SCV000319656.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: show 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) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: unknown Observation 1 Collection method: clinical testing Allele origin: germline Affected status: unknown

Benign (Jan 30, 2025) N Not contributing to aggregate classification	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	RASopathy	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000659055.9 First in ClinVar: Dec 26, 2017 Last updated: Feb 25, 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

Benign (Apr 01, 2023) N Not contributing to aggregate classification	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2)	not provided	CeGaT Center for Human Genetics Tuebingen Accession: SCV004146969.18 First in ClinVar: Nov 20, 2023 Last updated: Oct 25, 2025	Comment: show RAF1: BP4, BP7, BS1, BS2 (less) Observation: 1 Collection method: clinical testing Allele origin: germline Affected status: yes more Observation 1 Collection method: clinical testing Allele origin: germline Affected status: yes Number of individuals with the variant: 1

Comment:

The filtering allele frequency of the c.1914G>A (p.Thr638=) variant in the RAF1 gene is 0.926% (174/16512) of South Asian 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 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:

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:

p.Thr638Thr in exon 17 of RAF1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 1% (174/16512) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broa dinstitute.org/; dbSNP rs144876026).

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.

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
https://erepo.clinicalgenome.org/evrepo/ui/interpretation/5dd1c397-b2a2-4954-bbbb-583d4a4576dc	-	-	-	-

Text-mined citations for rs144876026 ...

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 26, 2025

ClinVar Genomic variation as it relates to human health

NM_002880.4(RAF1):c.1914G>A (p.Thr638=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Citations for germline classification of this variant

Text-mined citations for rs144876026 ...