Submissions for variant NM_002880.4(RAF1):c.212A>G (p.Asn71Ser)

gnomAD frequency: 0.00029  dbSNP: rs184022679

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen RASopathy Variant Curation Expert Panel	RCV000461248	SCV000616420	benign	RASopathy	2017-04-03	reviewed by expert panel	curation	The filtering allele frequency of the c.212A>G (p.Asn71Ser) variant in the RAF1 gene is 0.14% for Latino chromosomes by the Exome Aggregation Consortium (24/11578 with 95% CI), which is a high enough frequency to be classified as benign based on thresholds defined by the ClinGen RASopathy Expert panel for autosomal dominant RASopathy variants (BA1).
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000037686	SCV000061348	uncertain significance	not specified	2013-01-16	criteria provided, single submitter	clinical testing	Variant classified as Uncertain Significance - Favor Benign. The Asn71Ser varian t in RAF1 has not been previously reported in the literature nor previously been identified by our laboratory. This variant has been identified in 0.01% (1/8600 ) of European American chromosomes from a broad population by the NHLBI Exome Se quencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs184022679). Computa tional analyses (biochemical amino acid properties, conservation, AlignGVGD, Pol yPhen2, and SIFT) suggest that the Asn71Ser variant may not impact the normal fu nction of the protein, though this information is not predictive enough to rule out pathogenicity. Of note, the Shrew (a species in the Mammalian class) also ca rries a serine (Ser) at amino acid position 71 in the RAF1 gene. In summary, add itional information is needed to fully assess the clinical significance of this variant.
GeneDx	RCV000586687	SCV000209004	benign	not provided	2016-06-06	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000461248	SCV000562250	likely benign	RASopathy	2024-01-25	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000037686	SCV000698125	benign	not specified	2021-07-27	criteria provided, single submitter	clinical testing	Variant summary: RAF1 c.212A>G (p.Asn71Ser) results in a conservative amino acid change located in the Raf-like Ras-binding (IPR003116) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00025 in 251492 control chromosomes, predominantly at a frequency of 0.0014 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 56 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. To our knowledge, no occurrence of c.212A>G in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. Four other ClinVar submitters (evaluation after 2014) including an expert panel (ClinGen RASopathy Variant Curation Expert Panel) cite the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV000620637	SCV000740074	benign	Cardiovascular phenotype	2017-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CeGaT Center for Human Genetics Tuebingen	RCV000586687	SCV002821163	likely benign	not provided	2023-03-01	criteria provided, single submitter	clinical testing	RAF1: BS1
PreventionGenetics, part of Exact Sciences	RCV004532499	SCV004752576	likely benign	RAF1-related disorder	2021-12-15	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).