Variant: NM_002880.3(RAF1):c.779C>T (p.Thr260Ile)

CA351736

222774 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: d61ef783-d3ed-4577-9f3c-3f2b6c65e7be

HGVS expressions

NM_002880.3:c.779C>T
NM_002880.3(RAF1):c.779C>T (p.Thr260Ile)
NC_000003.12:g.12604191G>A
CM000665.2:g.12604191G>A
NC_000003.11:g.12645690G>A
CM000665.1:g.12645690G>A
NC_000003.10:g.12620690G>A
NG_007467.1:g.64989C>T
NM_001354689.1:c.779C>T
NM_001354690.1:c.779C>T
NM_001354691.1:c.536C>T
NM_001354692.1:c.536C>T
NM_001354693.1:c.680C>T
NM_001354694.1:c.536C>T
NM_001354695.1:c.437C>T
NR_148940.1:n.1194C>T
NR_148941.1:n.1194C>T
NR_148942.1:n.1194C>T
NM_001354689.3:c.779C>T
NM_001354690.2:c.779C>T
NM_001354691.2:c.536C>T
NM_001354692.2:c.536C>T
NM_001354693.2:c.680C>T
NM_001354694.2:c.536C>T
NM_001354695.2:c.437C>T
NR_148940.2:n.1110C>T
NR_148941.2:n.1110C>T
NR_148942.2:n.1110C>T
ENST00000251849.8:c.779C>T
ENST00000416093.1:c.*357C>T
ENST00000423275.5:c.*456C>T
ENST00000432427.2:n.416C>T
ENST00000442415.6:c.779C>T
ENST00000465826.5:n.23C>T
ENST00000491290.1:n.300C>T

Uncertain Significance

The Expert Panel has overridden the computationally generated classification - "Likely Pathogenic"

• Met criteria codes: PS3 PP2 PM2 PM1

• Not Met criteria codes: PS4 PP3 PM5

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.779C>T (p.Thr260Ile) variant in RAF1 was absent from large population databases (PM2; gnomad.broadinstitute.org). It occurs in the CR2 domain of the protein, which has been identified as a region important for protein function (PM1, 29493581). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 20679480). The variant is located in the RAF1 gene, which has been defined by the ClinGen RASopathy Expert Panel as a gene with a low rate of benign missense variants and pathogenic variants are common (PP2; PMID: 29493581). Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. This variant has been observed in multiple probands who lacked consistent RASopathy phenotypes; however, many probands presented with cardiomyopathy (PMID: 17603483; Blueprint Genetics internal data, SCV000264163.2; Invitae internal data, SCV000824563.1; Ambry internal data, SCV000740058.2; GeneDx internal data, SCV000582743.4). Although criteria suggest that this variant is likely pathogenic given its location and in vitro functional studies, the lack of clear clinical presentations of a RASopathy phenotype supports that this variant is of uncertain significance at this time. RASopathy-specific ACMG/AMP criteria applied: PS3, PM1, PM2, PP2.

Met criteria codes

• PS3: Kinase activity assay from Molzan et al. 2010 (PMID: 20679480) demonstrated increased phosphorylation of ERK compared to WT.
• PP2: RAF1 is a missense-constrained gene.
• PM2: Absent from gnomAD v2 and v3.
• PM1: Occurs in the CR2 domain [aa 251-266/ex7].

Not Met criteria codes

• PS4: One case from Invitae had short stature and a broad neck, but no diagnosis of a RASopathy (SCV000824563.1). Other cases had only HCM (PMID: 17603483; GeneDx internal data, SCV000582743.4; Ambry internal data, SCV000740058.2; Blueprint internal data, SCV000264163.2).
• PP3: REVEL score 0.623. Highly conserved (no animals in UCSC database have Ile at this position). Splicing is not predicted to be impacted.
• PM5: Not applied since PM1 is already met. 2 variants in this codon are reported in ClinVar, but neither have been evaluated by the VCEP and have only 1 submitter each.

Approved on: 2020-03-09

Published on: 2020-03-09