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

Variant: NM_004333.5(BRAF):c.1406G>A (p.Gly469Glu)

CA279970

13974 (ClinVar)

Gene: BRAF
Condition: cardiofaciocutaneous syndrome
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: f75f3f8b-6c9c-41a1-9cee-4716d67229dd

HGVS expressions

NM_004333.5:c.1406G>A
NM_004333.5(BRAF):c.1406G>A (p.Gly469Glu)
NM_004333.4:c.1406G>A
NM_001354609.1:c.1406G>A
NR_148928.1:n.1711G>A
ENST00000288602.10:c.1406G>A
ENST00000496384.6:n.229G>A
ENST00000497784.1:n.1441G>A
NC_000007.14:g.140781602C>T
CM000669.2:g.140781602C>T
NC_000007.13:g.140481402C>T
CM000669.1:g.140481402C>T
NC_000007.12:g.140127871C>T
NG_007873.3:g.148163G>A

Pathogenic

Met criteria codes 6
PS3 PP3 PP2 PM1 PM2 PS2_Very Strong

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1406G>A (p.Gly469Glu) variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VeryStrong; PMID 18042262, 16474404). In vitro functional studies provide some evidence that the p.Gly469Glu variant may impact protein function (PS3; 16474404). This variant was absent from large population studies (PM2; ExAC, http://exac.broadinstitute.org). The variant is located in the BRAF gene, 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). Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581). Computational prediction tools and conservation analysis suggest that the p.Gly469Glu variant may impact the protein (PP3). 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): PP2, PP3, PM1, PM2, PS2_VeryStrong, PS3.
Met criteria codes
PS3
In vitro functional studies provide some evidence that the p.G469E variant may impact protein function (PS3; 16474404).
PP3
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
Furthermore, this variant is in a location which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; PMID 29493581).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PS2_Very Strong
The p.G469E variant in BRAF has been reported in the literature as a confirmed de novo occurrence in at least 2 patients with clinical features of a RASopathy (PS2_VS; PMID 18042262, 16474404).
Approved on: 2017-04-03
Published on: 2018-12-10
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