ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.995T>C (p.Val332Ala) (rs370243307)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000471101 SCV000616424 uncertain significance Rasopathy 2017-04-03 reviewed by expert panel curation The c.935T>C p.Val312Ala variant has been identified in 2 probands with clinical features of RASopathies (PS4 not met; GeneDx, Partners LMM internal data; GTR ID's: 26957, 21766; ClinVar SCV000200036.4; SCV000209006.12). Computational prediction tools and conservation analysis suggest that the p.Val312Ala variant does not impact the protein (BP4). In summary, the clinical significance of the p.Val312Ala variant is uncertain. RASopathy-specific ACMG/AMP criteria applied (PMID:29493581): BP4.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000151711 SCV000200036 uncertain significance not specified 2013-12-05 criteria provided, single submitter clinical testing The Val312Ala variant in RAF1 has not been previously reported in other families with clinical features of Noonan spectrum disorders, but has been identified in 1/8600 European American chromosomes by the NHLBI Exome Sequencing Project (htt p:// Of note, another variant at this position, Val31 2Gly, has been identified in one fetus with abnormal ultrasound findings and a n ormal karyotype (Croonen 2013). Valine (Val) at position 312 is not conserved in mammals or across evolutionarily distant species, and several mammals and other species (including cow, sheep, antelope, and fish species) have an alanine (Ala ) at this position, suggesting that this change may be tolerated. Other computat ional analyses (biochemical amino acid properties, AlignGVGD, PolyPhen2, and SIF T) suggest that the Val312Ala variant may not impact the protein. In summary, ad ditional information is needed to fully assess the clinical significance of the Val312Ala variant.
GeneDx RCV000680307 SCV000209006 likely benign not provided 2017-05-16 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000246938 SCV000318466 likely benign Cardiovascular phenotype 2019-06-21 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000471101 SCV000552094 likely benign Rasopathy 2020-11-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000151711 SCV000920138 likely benign not specified 2018-03-26 criteria provided, single submitter clinical testing Variant summary: RAF1 c.935T>C (p.Val312Ala) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 277138 control chromosomes. The observed variant frequency is approximately 5.77 fold above the estimated maximal expected allele frequency for a pathogenic variant in RAF1 causing Noonan Syndrome and Related Conditions phenotype (2.5e-05), strongly suggesting that the variant is benign. c.935T>C has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions. These reports do not provide unequivocal conclusions about an association of the variant with Noonan Syndrome and Related Conditions. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (1 likely benign, 2 VUS). Based on the evidence outlined above, the variant was classified as likely benign.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV001256890 SCV001433388 uncertain significance Familial hypertrophic cardiomyopathy 1 2019-12-30 criteria provided, single submitter clinical testing

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