ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.2104T>C (p.Tyr702His) (rs727505381)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000156979 SCV000206701 pathogenic Noonan syndrome 2013-03-26 no assertion criteria provided clinical testing
Blueprint Genetics RCV000159124 SCV000928250 pathogenic not provided 2019-02-25 criteria provided, single submitter clinical testing
GeneDx RCV000159124 SCV000209068 pathogenic not provided 2016-11-17 criteria provided, single submitter clinical testing p.Tyr702His (TAT>CAT): c.2104 T>C in exon 13 of the SOS1 gene (NM_005633.3). The Y702H missense mutation in the SOS1 gene has been reported previously in association with Noonan syndrome (Tartaglia et al., 2007). The NHLBI ESP Exome Variant Server reports that Y702H was not observed in approximately 6,000 individuals of European and African American backgrounds, indicating it is not a common benign variant in these populations. The majority of SOS1 mutations are found in exon 11 (52%), followed by exons 7 and 17 (14% each).The variant is found in NOONAN panel(s).
Invitae RCV000817385 SCV000957940 pathogenic Rasopathy 2018-09-19 criteria provided, single submitter clinical testing This sequence change replaces tyrosine with histidine at codon 702 of the SOS1 protein (p.Tyr702His). The tyrosine residue is highly conserved and there is a moderate physicochemical difference between tyrosine and histidine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in several individuals affected with Noonan syndrome (PMID: 22190897, 25862627, 17143282) and was observed to be de novo in two of these individuals (PMID: 23885229, 17586837). This variant was also reported to segregate in a family with features suggestive of Noonan syndrome (PMID: 20683980). ClinVar contains an entry for this variant (Variation ID: 40696). Experimental studies have shown that this missense change increases ERK phosphorylation in vitro (PMID: 23487764). For these reasons, this variant has been classified as Pathogenic.

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