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]
  • Gene obtained from curated document aligns with the Allele Registry but not with ClinVar data
  • No CSPEC related information was provided by the message!
  • No CSPEC computer assertion could be determined for this classification!
  • See Evidence submitted by expert panel for details.

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

CA241481

40584 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 1128f941-c33c-438d-a44d-f5a0c76c3440
Approved on: 2019-06-27
Published on: 2024-08-23

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
ENST00000416093.2:c.94A>G
ENST00000423275.6:c.94A>G
ENST00000491290.2:n.471A>G
ENST00000684903.1:c.94A>G
ENST00000685348.1:c.94A>G
ENST00000685437.1:c.94A>G
ENST00000685653.1:c.94A>G
ENST00000685738.1:c.94A>G
ENST00000685740.1:c.94A>G
ENST00000685959.1:c.94A>G
ENST00000686409.1:n.385A>G
ENST00000686455.1:n.457A>G
ENST00000686479.1:n.465A>G
ENST00000686762.1:c.94A>G
ENST00000687257.1:n.429A>G
ENST00000687326.1:c.94A>G
ENST00000687348.1:c.94A>G
ENST00000687923.1:c.94A>G
ENST00000687940.1:n.471A>G
ENST00000688269.1:n.393A>G
ENST00000688444.1:n.420A>G
ENST00000688543.1:c.94A>G
ENST00000688625.1:c.94A>G
ENST00000688753.1:c.94A>G
ENST00000688779.1:n.425A>G
ENST00000688803.1:n.424A>G
ENST00000689033.1:c.94A>G
ENST00000689097.1:c.94A>G
ENST00000689226.1:c.94A>G
ENST00000689389.1:c.94A>G
ENST00000689418.1:c.94A>G
ENST00000689481.1:c.94A>G
ENST00000689540.1:n.244A>G
ENST00000689876.1:c.94A>G
ENST00000689914.1:c.94A>G
ENST00000690397.1:c.94A>G
ENST00000690460.1:c.94A>G
ENST00000690625.1:n.397A>G
ENST00000691396.1:c.94A>G
ENST00000691718.1:c.94A>G
ENST00000691724.1:c.94A>G
ENST00000691779.1:c.94A>G
ENST00000691899.1:c.94A>G
ENST00000692093.1:c.94A>G
ENST00000692311.1:n.467A>G
ENST00000692558.1:n.459A>G
ENST00000692773.1:c.94A>G
ENST00000692777.1:n.422A>G
ENST00000692830.1:c.94A>G
ENST00000692959.1:c.94A>G
ENST00000693069.1:c.94A>G
ENST00000693312.1:c.-18-6566A>G
ENST00000693664.1:c.94A>G
ENST00000693705.1:c.94A>G
ENST00000251849.9:c.94A>G
ENST00000442415.7:c.94A>G
ENST00000251849.8:c.94A>G
ENST00000416093.1:c.94A>G
ENST00000423275.5:c.94A>G
ENST00000442415.6:c.94A>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
NM_001354689.3:c.94A>G
NM_001354690.2:c.94A>G
NM_001354691.2:c.-37A>G
NM_001354692.2:c.-37A>G
NM_001354693.2:c.94A>G
NM_001354694.2:c.-37A>G
NM_001354695.2:c.-37A>G
NR_148940.2:n.425A>G
NR_148941.2:n.425A>G
NR_148942.2:n.425A>G
NM_001354690.3:c.94A>G
NM_001354691.3:c.-37A>G
NM_001354692.3:c.-37A>G
NM_001354693.3:c.94A>G
NM_001354694.3:c.-37A>G
NM_001354695.3:c.-37A>G
NM_002880.4:c.94A>G
NR_148940.3:n.425A>G
NR_148941.3:n.425A>G
NR_148942.3:n.425A>G
More

Benign

Met criteria codes 5
BS2 BS1 BP5 BP4 PP2
Not Met criteria codes 19
BS3 BS4 BP7 BP2 BP3 BP1 PVS1 PS3 PS2 PS4 BA1 PP4 PP3 PP1 PM1 PM3 PM4 PM6 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
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
BS2
Invitae: Observed this variant in a supposedly unaffected relative
BS1
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).
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
Not Met criteria codes
BS3
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
BP7
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
BP3
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
PVS1
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
PS2
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.
BA1
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PP4
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
PP1
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
PM3
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
PM6
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
Curation History
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