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]

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Variant: NM_004333.6(BRAF):c.1411G>T (p.Val471Phe)

CA281968

40367 (ClinVar)

Gene: BRAF

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

Link to MONDO

UUID: 0fbf3e7d-b10c-48d4-8d20-1829cc00cf42

Approved on: 2020-06-25

Published on: 2020-07-01

HGVS expressions

NM_004333.6:c.1411G>T

NM_004333.6(BRAF):c.1411G>T (p.Val471Phe)

NM_004333.4:c.1411G>T

NM_001354609.1:c.1411G>T

NM_004333.5:c.1411G>T

NR_148928.1:n.1716G>T

NM_001354609.2:c.1411G>T

NM_001374244.1:c.1531G>T

NM_001374258.1:c.1531G>T

ENST00000288602.10:c.1411G>T

ENST00000496384.6:n.234G>T

ENST00000497784.1:n.1446G>T

NC_000007.14:g.140781597C>A

CM000669.2:g.140781597C>A

NC_000007.13:g.140481397C>A

CM000669.1:g.140481397C>A

NC_000007.12:g.140127866C>A

NG_007873.3:g.148168G>T

Pathogenic

PS3 PS4_Supporting PP2 PP3 PM1 PM2 PM6

PM5

Evidence Links 3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Criteria Specifications for this VCEP

Evidence submitted by expert panel

RASopathy VCEP

The c.1411G>T (p.Val471Phe) variant in BRAF was absent from large population studies (PM2; gnomAD.broadinstitute.org). It has been identified in at least 2 individuals diagnosed with RASopathies (PS4_Supporting; PMID: 22495831, 30937965). One of these cases was shown to be a de novo occurrence without maternity or paternity confirmed (PM6). In vitro functional studies provide some evidence that the p.Val471Phe variant may impact protein function (PS3; PMID: 25348715). Furthermore, the variant is in a location that has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; 29493581). Computational prediction tools and conservation analysis suggest that the p.Val471Phe variant in BRAF may impact the protein (PP3). This variant is located in BRAF, 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 autosomal dominant RASopathies. RASopathy-specific ACMG/AMP criteria applied (PMID: 29493581): PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3.

PS3

In vitro functional assays in 293T cells demonstrate that this variant causes increased activation of ERK.

In vitro functional assays in 293T cells demonstrate that this variant causes increased activation of ERK. PubMed:25348715

PS4_Supporting

Seen in 2 probands diagnosed with RASopathies.

PubMed:30937965

PubMed:22495831

PP2

BRAF is a missense-constrained gene (PMID: 29493581).

PP3

REVEL score 0.975. Entirely conserved in UCSC database. (This variant may impact splicing, however changes to splicing are not expected to align with the GoF disease mechanism for BRAF-associated RASopathy.)

PM1

This variant occurs in the P-loop region (aa 459-474), which has been defined by the ClinGen RASopathy Expert Panel to be a mutational hotspot or domain of BRAF (PM1; 29493581).

PM2

Absent from both gnomAD v2.1.1 and v3 (PM2).

PM6

Seen de novo in one proband with Noonan syndrome (maternity/paternity not tested).

PM5

There is 1 variant in the same codon (c.1411G>A (p.Val471Ile)), however this code was not used since PM1 is already met.

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