ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.122G>A (p.Arg41Gln) (rs145611571)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037673 SCV000061335 likely benign not specified 2018-10-10 criteria provided, single submitter clinical testing The p.Arg41Gln variant in RAF1 has been identified by our laboratory in 2 indivi duals with clinical features of a RASopathy and segregated with disease in 1 aff ected relative; however, this variant has also been identified in 0.05% (17/3442 0) of Latino chromosomes and 0.03% (44/126734) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org) and, therefore, it is classified as likely b enign. ACMG/AMP Criteria applied: BS1.
GeneDx RCV000680304 SCV000209003 benign not provided 2016-02-29 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 RCV000253580 SCV000320377 likely benign Cardiovascular phenotype 2020-03-19 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification
Invitae RCV000463359 SCV000552090 uncertain significance Rasopathy 2020-10-29 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 41 of the RAF1 protein (p.Arg41Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs145611571, ExAC 0.02%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with a RAF1-related disease. ClinVar contains an entry for this variant (Variation ID: 40586). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease,Montreal Heart Institute RCV000624707 SCV000740652 uncertain significance Primary familial dilated cardiomyopathy 2016-10-19 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000680304 SCV000861761 uncertain significance not provided 2018-06-25 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000680304 SCV000884443 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing The RAF1 c.122G>A; p.Arg41Gln variant (rs145611571), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.03% (identified on 75 out of 277,246 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 279925). The arginine at position 41 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Arg41Gln variant on protein structure and function make conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging). Based on the available information, the clinical significance of the p.Arg41Gln variant cannot be determined with certainty.
Mendelics RCV000987120 SCV001136325 uncertain significance LEOPARD syndrome 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001149006 SCV001309930 uncertain significance Noonan syndrome 5 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Clinical Services Laboratory,Illumina RCV000987120 SCV001309931 benign LEOPARD syndrome 2 2018-01-13 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037673 SCV001426962 likely benign not specified 2020-07-06 criteria provided, single submitter clinical testing Variant summary: RAF1 c.122G>A (p.Arg41Gln) results in a 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 0.00028 in 252090 control chromosomes, predominantly at a frequency of 0.00046 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 18 fold of 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 a benign polymorphism found primarily in populations of Latino origin. c.122G>A has been reported in the literature in at least one individual with autism (Kelleher_2012). The report does not provide unequivocal conclusions about 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. Ten ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (7x), likely benign (1x) and benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001261025 SCV001438423 uncertain significance Noonan syndrome no assertion criteria provided clinical testing

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