Evidence Repository - Clinical Genome Resources

The ClinGen Evidence Repository is an FDA-recognized human genetic variant database containing expert-curated assertions regarding variants' pathogenicity and supporting evidence summaries. [Disclaimer]

Link to SEPIO compliant JSON-LD document

Variant: NM_002880.3(RAF1):c.776C>A (p.Ser259Tyr)

CA134750

44633 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: b0b89194-26bd-44cc-967f-db86e0e33549

HGVS expressions

NM_002880.3:c.776C>A

NM_002880.3(RAF1):c.776C>A (p.Ser259Tyr)

NC_000003.12:g.12604194G>T

CM000665.2:g.12604194G>T

NC_000003.11:g.12645693G>T

CM000665.1:g.12645693G>T

NC_000003.10:g.12620693G>T

NG_007467.1:g.64986C>A

NM_001354689.1:c.776C>A

NM_001354690.1:c.776C>A

NM_001354691.1:c.533C>A

NM_001354692.1:c.533C>A

NM_001354693.1:c.677C>A

NM_001354694.1:c.533C>A

NM_001354695.1:c.434C>A

NR_148940.1:n.1191C>A

NR_148941.1:n.1191C>A

NR_148942.1:n.1191C>A

NM_001354689.3:c.776C>A

NM_001354690.2:c.776C>A

NM_001354691.2:c.533C>A

NM_001354692.2:c.533C>A

NM_001354693.2:c.677C>A

NM_001354694.2:c.533C>A

NM_001354695.2:c.434C>A

NR_148940.2:n.1107C>A

NR_148941.2:n.1107C>A

NR_148942.2:n.1107C>A

ENST00000251849.8:c.776C>A

ENST00000416093.1:c.*354C>A

ENST00000423275.5:c.*453C>A

ENST00000432427.2:n.413C>A

ENST00000442415.6:c.776C>A

ENST00000465826.5:n.20C>A

ENST00000491290.1:n.297C>A

Pathogenic

PS2 PP2 PM1 PM2 PS4_Moderate

PM5

Evidence Links 2

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.776C>A (p.Ser259Tyr) variant in RAF1 was absent from large population studies (PM2; gnomAD, http://gnomad.broadinstitute.org). It has been reported in 3 probands with clinical features of Noonan syndrome (PS4_Moderate; PMIDs: 31030682, 26918529, GeneDx internal data). In one proband, the variant occurred de novo with parentage confirmation (PS2; PMID: 31030682). The c.776C>A (p.Ser259Tyr) variant occurs in the CR2 activation domain of RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a region important for protein function (PM1; PMID 29493581). A different pathogenic missense variant has been previously identified at this codon of RAF1 supporting this residue is critical to the function of the protein (PM5 not applied; ClinVar 40601). The variant is located in RAF1, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic missense variants are common (PP2; PMID: 29493581). In summary, this variant meets criteria to be classified as pathogenic for RASopathies in an autosomal dominant manner. Rasopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PS4_Moderate, PS2, PM1, PP2.

PS2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PP2

No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

PM1

CR2 domain

PM2

Absent from gnomAD

PS4_Moderate

Identified in a patient with Hypertrophic cardiomyopathy, dysmorphic features. Clinically diagnosed with Noonan syndrome. No parental carrier testing. (GeneDx internal data). Identified in 3 month old baby with NS, variant listed as VOUS in ClinVar but LMM is in the process of reclassifying (SCV000061364.6) may be the same case described in PMID 26918529.

PubMed:26918529

PubMed:31030682

PM5

Not met because PM1 is applicable, ClinVar: 40601

Approved on: 2020-05-18

Published on: 2020-05-21

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