ClinVar Miner

Submissions for variant NM_001354689.3(RAF1):c.639T>C (p.Thr213=) (rs397516823)

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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 RCV001030082 SCV001192874 benign Rasopathy 2019-11-04 reviewed by expert panel curation The c.639T>C (p.Thr213Thr) variant in RAF1 is classified as benign because it has been identified in 0.05616% (lower bound of the 95% CI of 28/35434) of Latino alleles in gnomAD (BA1; It was observed in an individual with an alternate molecular basis for disease (BP5; SCV000061357.6). It does not alter an amino acid residue, is not located within the splice consensus site, and computational splice prediction tools do not predict an impact to splicing (BP4, BP7). ACMG/AMP Criteria applied: BA1, BP4, BP5, BP7.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000037695 SCV000061357 likely benign not specified 2012-02-15 criteria provided, single submitter clinical testing Thr213Thr in exon 6 of RAF1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and it is not located wi thin the splice consensus sequence.
Invitae RCV001030082 SCV000659062 likely benign Rasopathy 2020-10-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000621888 SCV000740149 likely benign Cardiovascular phenotype 2017-05-05 criteria provided, single submitter clinical testing Synonymous alterations with insufficient evidence to classify as benign
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000727917 SCV000855426 uncertain significance not provided 2017-07-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000037695 SCV000920139 benign not specified 2018-04-02 criteria provided, single submitter clinical testing Variant summary: RAF1 c.639T>C alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was observed with an allele frequency of 0.0001 in 246250 control chromosomes (gnomAD). The observed variant frequency within Latino control individuals in the gnomAD database is approximately 28-fold higher than 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.639T>C in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submssion from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as "likely benign." Based on the evidence outlined above, the variant was classified as benign.

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