ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.1201G>A (p.Asp401Asn) (rs559632360)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen RASopathy Variant Curation Expert Panel RCV000522135 SCV000616485 benign Rasopathy 2017-04-18 reviewed by expert panel curation The filtering allele frequency of the c.1141G>A (p.Asp381Asn) variant in the RAF1 gene is 0.162% (36/16508) of South Asian chromosomes by the Exome Aggregation Consortium, which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert Panel (BA1; PMID:29493581)
GeneDx RCV000159079 SCV000209022 benign not specified 2017-02-07 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.
Invitae RCV000867203 SCV001008402 likely benign not provided 2018-06-21 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159079 SCV001361782 benign not specified 2019-07-15 criteria provided, single submitter clinical testing Variant summary: RAF1 c.1141G>A (p.Asp381Asn) results in a conservative amino acid change located in the Serine-threonine/tyrosine-protein kinase, catalytic domain (IPR001245) of the encoded protein sequence. Five 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 251374 control chromosomes, predominantly at a frequency of 0.0023 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 90 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 South Asian origin. c.1141G>A has been reported in the literature in an individual with suspected RASopathy, presenting with "congenital hypoplasia of the lung, congenital anomaly of ribs and sternum, polyhydramnios, hydrops fetalis, died on DOL 12," however, authors classified the variant as likely benign (Bhoj_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission (evaluation after 2014) from an expert panel (ClinGen) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000522135 SCV001598755 likely benign Rasopathy 2020-10-05 criteria provided, single submitter clinical testing
Service de Génétique Moléculaire,Hôpital Robert Debré RCV001261134 SCV001438541 uncertain significance Noonan syndrome with multiple lentigines; Noonan syndrome no assertion criteria provided clinical testing

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