7-140781617-C-T
Variant summary
Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PS3PS2PM1PP3PP2PS4_SupportingPM6PM2
This summary comes from the ClinGen Evidence Repository: The c.1391G>A (p.Gly464Glu) variant in BRAF has been observed in 2 probands with phenotypes consistent with cardiofaciocutaneous syndrome (PS4_Supporting; LMM internal data, SCV000197160.4; GeneDx internal data, SCV000057209.13). One of these cases was de novo with maternity and paternity confirmed, while the other was de novo without confirmation of maternity or paternity (PS2, PM6). The p.Gly464Glu variant was absent from large population studies (PM2; gnomad.broadinstitute.org). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID:25155755). It occurs in the P-loop domain of the protein, which has been identified as an important region for protein function (PM1; 29493581). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein (PP3). 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 variants are common (PP2; PMID:29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied: PS2, PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3. LINK:https://erepo.genome.network/evrepo/ui/classification/CA250636/MONDO:0021060/004
Frequency
Consequence
NM_004333.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 17 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
BRAF | ENST00000644969.2 | c.1511G>A | p.Gly504Glu | missense_variant | Exon 12 of 20 | NM_001374258.1 | ENSP00000496776.1 | |||
BRAF | ENST00000646891.2 | c.1391G>A | p.Gly464Glu | missense_variant | Exon 11 of 18 | NM_004333.6 | ENSP00000493543.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not provided Pathogenic:2
The G464E missense mutation has not been reported as a mutation, but neither has it been published as a benign polymorphism. The position at which this mutation occurs is highly conserved across species and other missense mutations at this position (G464V, G464R) have been previously reported in the literature (Rodriguez-Viciana et al., 2008, Cave et al., 2008). -
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RASopathy Pathogenic:2
The c.1391G>A (p.Gly464Glu) variant in BRAF has been observed in 2 probands with phenotypes consistent with cardiofaciocutaneous syndrome (PS4_Supporting; LMM internal data, SCV000197160.4; GeneDx internal data, SCV000057209.13). One of these cases was de novo with maternity and paternity confirmed, while the other was de novo without confirmation of maternity or paternity (PS2, PM6). The p.Gly464Glu variant was absent from large population studies (PM2; gnomad.broadinstitute.org). In vitro functional assays indicate that this variant may impact protein function (PS3; PMID: 25155755). It occurs in the P-loop domain of the protein, which has been identified as an important region for protein function (PM1; 29493581). Computational prediction tools and conservation analyses also suggest that this variant may impact the protein (PP3). 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 variants are common (PP2; PMID: 29493581). Of note, this variant has also been observed in association with somatic malignancies; however, analysis and classification of somatic variation is currently not used to inform germline classifications for the RASopathies. In summary, this variant meets criteria to be classified as pathogenic for autosomal dominant RASopathy. RASopathy-specific ACMG/AMP criteria applied: PS2, PS3, PS4_Supporting, PM1, PM2, PM6, PP2, PP3. -
For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly464 amino acid residue in BRAF. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18413255, 18039235, 21062266, 19376813, 23680146). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt BRAF protein function. This variant has been observed in individual(s) with clinical features of Noonan syndrome (Invitae). ClinVar contains an entry for this variant (Variation ID: 13964). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with glutamic acid at codon 464 of the BRAF protein (p.Gly464Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. -
Noonan syndrome;C1275081:Cardio-facio-cutaneous syndrome Pathogenic:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Carcinoma of colon Pathogenic:1
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Cardio-facio-cutaneous syndrome Uncertain:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at