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]
  • See Evidence submitted by expert panel for details.

Variant: NM_002880.3(RAF1):c.1193G>T (p.Arg398Leu)

CA235336

40614 (ClinVar)

Gene: RAF1
Condition: RASopathy
Inheritance Mode: Autosomal dominant inheritance
Link to MONDO
UUID: 54e513e4-3d82-4530-8f42-82522d750073
Approved on: 2019-12-05
Published on: 2019-12-05

HGVS expressions

NM_002880.3:c.1193G>T
NM_002880.3(RAF1):c.1193G>T (p.Arg398Leu)
NC_000003.12:g.12591708C>A
CM000665.2:g.12591708C>A
NC_000003.11:g.12633207C>A
CM000665.1:g.12633207C>A
NC_000003.10:g.12608207C>A
NG_007467.1:g.77472G>T
ENST00000423275.6:c.*858G>T
ENST00000432427.3:c.510G>T
ENST00000465826.6:n.784G>T
ENST00000475353.2:n.1115G>T
ENST00000491290.2:n.1553G>T
ENST00000494557.2:n.1004G>T
ENST00000684903.1:c.*870G>T
ENST00000685348.1:c.*870G>T
ENST00000685437.1:c.1094G>T
ENST00000685653.1:c.1193G>T
ENST00000685738.1:c.*157G>T
ENST00000686409.1:n.2244G>T
ENST00000686455.1:n.1556G>T
ENST00000686762.1:c.1193G>T
ENST00000687257.1:n.1429G>T
ENST00000687326.1:c.*127G>T
ENST00000687486.1:c.385G>T
ENST00000687505.1:n.1311G>T
ENST00000687923.1:c.1082G>T
ENST00000687940.1:n.1570G>T
ENST00000688269.1:n.1789G>T
ENST00000688326.1:c.626G>T
ENST00000688444.1:n.1519G>T
ENST00000688543.1:c.1094G>T
ENST00000688625.1:c.*771G>T
ENST00000688803.1:n.1424G>T
ENST00000688914.1:n.179G>T
ENST00000689097.1:c.*870G>T
ENST00000689389.1:c.1193G>T
ENST00000689418.1:c.*870G>T
ENST00000689481.1:c.*870G>T
ENST00000689540.1:n.1343G>T
ENST00000689876.1:c.1193G>T
ENST00000689914.1:c.*127G>T
ENST00000690397.1:c.1082G>T
ENST00000690460.1:c.1181G>T
ENST00000690585.1:c.85G>T
ENST00000690625.1:n.1496G>T
ENST00000691396.1:c.*1045G>T
ENST00000691724.1:c.*150G>T
ENST00000691779.1:c.*771G>T
ENST00000691888.1:c.85G>T
ENST00000691899.1:c.1193G>T
ENST00000692069.1:n.1759G>T
ENST00000692093.1:c.1094G>T
ENST00000692311.1:n.2017G>T
ENST00000692558.1:n.1558G>T
ENST00000692773.1:c.*930G>T
ENST00000692830.1:c.*938G>T
ENST00000693069.1:c.*127G>T
ENST00000693312.1:c.968G>T
ENST00000693664.1:c.1193G>T
ENST00000693705.1:c.*870G>T
ENST00000251849.9:c.1193G>T
ENST00000442415.7:c.1253G>T
ENST00000251849.8:c.1193G>T
ENST00000423275.5:c.*870G>T
ENST00000432427.2:c.830G>T
ENST00000442415.6:c.1253G>T
ENST00000460610.1:n.150G>T
ENST00000465826.5:n.550G>T
ENST00000475353.1:n.361G>T
ENST00000494557.1:n.209G>T
NM_001354689.1:c.1253G>T
NM_001354690.1:c.1193G>T
NM_001354691.1:c.950G>T
NM_001354692.1:c.950G>T
NM_001354693.1:c.1094G>T
NM_001354694.1:c.1010G>T
NM_001354695.1:c.851G>T
NR_148940.1:n.1721G>T
NR_148941.1:n.1667G>T
NR_148942.1:n.1606G>T
NM_001354689.3:c.1253G>T
NM_001354690.2:c.1193G>T
NM_001354691.2:c.950G>T
NM_001354692.2:c.950G>T
NM_001354693.2:c.1094G>T
NM_001354694.2:c.1010G>T
NM_001354695.2:c.851G>T
NR_148940.2:n.1637G>T
NR_148941.2:n.1583G>T
NR_148942.2:n.1522G>T
NM_001354690.3:c.1193G>T
NM_001354691.3:c.950G>T
NM_001354692.3:c.950G>T
NM_001354693.3:c.1094G>T
NM_001354694.3:c.1010G>T
NM_001354695.3:c.851G>T
NM_002880.4:c.1193G>T
NR_148940.3:n.1637G>T
NR_148941.3:n.1583G>T
NR_148942.3:n.1522G>T
More

Pathogenic

Met criteria codes 6
PS2 PS4_Supporting PP2 PP3 PM6 PM2

Evidence Links 0

Expert Panel

Criteria Specification Information

Criteria Specifications for this VCEP
Evidence submitted by expert panel
RASopathy VCEP
The c.1193G>T (p.Arg398Leu) variant has been identified in at least 4 probands with variable phenotypic features with two of them having a clinical suspicion of Noonan syndrome (PS4 not met; Rady Children’s Institute for Genomic Medicine internal communications; SCV000209025.5; SCV000207671.1; SCV000552095.2). This variant was absent from large population studies (PM2). The variant is located in the RAF1 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; however, it is in a region that generally lacks pathogenic variants (PP2; PMID: 29493581). Computational prediction tools and conservation analysis suggest that the p.Arg398Leu variant may impact the protein (PP3). In summary, the clinical significance of the p.Arg398Leu variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): PM2, PP2, PP3.
Met criteria codes
PS2
1 proband born premature presented with: hydrops fetalis, anuria, patent ductus arteriosus, hypophosphatemia, patent foramen ovale, esophageal atresia, acute kidney injury. Found via wgs, de novo (mat and pat confirmed). (internal communications)
PS4_Supporting
Seen in 3 patients, 2 w/o clinical info -1 exom case in a male patient with speech delay, ASD, seizure-like activity, hydrocephalus, hypoplasia of the corpus callosum and a clinical dx of NS (SCV000209025.5) -1 proband with DD, 10th percentile for height, 1 CAL, low set ears, telecanthus, epicanthal folds, concern for NS. Parents tested by Sanger, and was de novo (SCV000207671.1).
PP2
The variant is located in the RAF1 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).
PP3
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
PM6
-1 proband with DD, 10th percentile for height, 1 CAL, low set ears, telecanthus, epicanthal folds, concern for NS. Parents tested by Sanger, and was de novo (SCV000207671.1).
PM2
No code specific comments provided, please refer to the summary above or general recommendations provided in the guideline
Curation History
The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. If you have questions about the information contained on this website, please see a health care professional.
¤ Powered by BCM's Genboree.