Variant: NM_002880.3(RAF1):c.94A>G (p.Ile32Val)

CA241481

40584 (ClinVar)

Gene: RAF1

Condition: RASopathy

Inheritance Mode: Autosomal dominant inheritance

UUID: 1128f941-c33c-438d-a44d-f5a0c76c3440

HGVS expressions

NM_002880.3:c.94A>G
NM_002880.3(RAF1):c.94A>G (p.Ile32Val)
NC_000003.12:g.12618628T>C
CM000665.2:g.12618628T>C
NC_000003.11:g.12660127T>C
CM000665.1:g.12660127T>C
NC_000003.10:g.12635127T>C
NG_007467.1:g.50552A>G
NM_001354689.1:c.94A>G
NM_001354690.1:c.94A>G
NM_001354691.1:c.-37A>G
NM_001354692.1:c.-37A>G
NM_001354693.1:c.94A>G
NM_001354694.1:c.-37A>G
NM_001354695.1:c.-37A>G
NR_148940.1:n.509A>G
NR_148941.1:n.509A>G
NR_148942.1:n.509A>G
ENST00000251849.8:c.94A>G
ENST00000416093.1:c.94A>G
ENST00000423275.5:c.94A>G
ENST00000442415.6:c.94A>G

Benign

The Expert Panel has overridden the computationally generated classification - "Uncertain Significance - Conflicting Evidence"

• Met criteria codes: BP5 BP4 PP2 BS2 BS1

• Not Met criteria codes: BP7 BP1 BP3 BP2 PS4 PS2 PS3 PP1 PP3 PM4 PM1 PM2 PM6 BA1 BS4 BS3

Expert Panel

RASopathy VCEP

Criteria Specification Information

Evidence submitted by expert panel

RASopathy VCEP

The c.94A>G (p.Ile32Val) variant in the RAF1 gene has been identified in patients who underwent testing for a RASopathy, however it has also been identified in multiple adults who did not have clinical features of a RASopathy (BS2, BP5; Invitae, EGL Diagnostics, GeneDx internal data; GTR Lab ID: 500031, 500060; SCV000287747.4, SCV000227277.5, SCV000209002.14). The filtering allele frequency of the p.Ile32Val variant is 0.017% for European (non-Finnish) genomes in the gnomAD database (8/31404 with 95% CI) which is a high enough frequency to be considered strong evidence that the variant is benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BS1). Computational prediction tools and conservation analysis suggest that the p.Ile32Val variant does not impact the protein (BP4). In summary, this variant meets criteria to be classified as benign. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BS2, BP5, BS1, BP4.

Met criteria codes

• BP5: EGL Diagnostics internal data: Variant was observed in a patient with restricted growth but incomplete features of RASopathy. The patient had two other pathogenic variants in a different gene in trans Invitae: The child with the Rasopathy and one adult with cardiomyopathy had pathogenic variants in other genes that would have explained their phenotype
• BP4: 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
• BS2: Invitae: Observed this variant in a supposedly unaffected relative
• BS1: African 6/24036 (0.0002496), European 22/126730 (0.0001736). Variant is just under the cutoff for BS1 (0.00025) but it does round up. Although this is not the filtering allele frequency, may want to consider using filtering allele frequency cutoffs.

Not Met criteria codes

• BP7: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BP2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS4: Invitae: We’ve seen this in 3 adults with various forms of cardiomyopathy, and one patient with a Rasopathy. The child with the Rasopathy and one adult with cardiomyopathy had pathogenic variants in other genes that would have explained their phenotype. We also observed this variant in a supposedly unaffected relative as well as in three patients who indicated that they were ‘affected’ but did not provide any phenotypic details. EGL Diagnostics: Observed varint in an infant with incomplete criteria for RASopathy and 2 other pathogenic variants in a different gene in trans. Also, observed this variant in 1 individual with cardiomyopathy with no molecular diagnosis.
• PS2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PP3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM2: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• PM6: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BA1: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS4: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
• BS3: No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline

Approved on: 2019-06-27

Published on: 2019-06-28