ClinVar Miner

Submissions for variant NM_005633.3(SOS1):c.1646C>A (p.Thr549Lys) (rs730881046)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159173 SCV000209118 likely pathogenic not provided 2014-04-08 criteria provided, single submitter clinical testing p.Thr549Lys (ACA>AAA): c.1646 C>A in exon 10 of the SOS1 gene (NM_005633.3). The T549K missense change in the SOS1 gene has been reported as a possibly pathogenic variant (Lepri et al., 2011). The T549K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is well conserved across species and is within the helical linker domain, which connects the pleckstrin homology (PH) domain and Ras exchanger motif (REM) (Lepri et al., 2011). Missense mutations in nearby residues (S548R, L550P, R552G, R552K, R552M, R552S, R552T, R552W) within the same domain have been reported in association with Noonan syndrome, supporting the functional importance of this region of the protein. Furthermore, the T549K variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, this variant is a strong candidate for a pathogenic mutation, however the possibility that it is a benign variant cannot be excluded. The variant is found in NOONAN panel(s).
Invitae RCV000696409 SCV000824970 uncertain significance Rasopathy 2018-05-09 criteria provided, single submitter clinical testing This sequence change replaces threonine with lysine at codon 549 of the SOS1 protein (p.Thr549Lys). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with symptoms of Noonan syndrome (PMID: 21387466). ClinVar contains an entry for this variant (Variation ID: 181553). 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. This missense change is located in a region of the SOS1 protein where a significant number of previously reported SOS1 missense mutations are found (PMID: 21387466). These observations suggest that a previously unreported missense substitution within this region may affect protein function, but experiments have not been done to test this possibility. 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.
Integrated Genetics/Laboratory Corporation of America RCV000780747 SCV000918259 uncertain significance not specified 2020-02-28 criteria provided, single submitter clinical testing Variant summary: SOS1 c.1646C>A (p.Thr549Lys) results in a non-conservative amino acid change in the encoded protein sequence. The variant is located at a helical linker (residues 548-558) that was suggested to be functionally important to maintain the structural stability of the protein (Lepri_2011 and PMID: 20133692), and variants in this linker, such as S548R, L550P, R552G/K/S/T, have been classified as disease variants by our laboratory and/or other clinical labs, indicating the functional importance of this protein region. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250870 control chromosomes (gnomAD). c.1646C>A has been reported in the literature in individuals affected with Noonan Syndrome and Related Conditions (Leach_2019, Lepri_2011). Specifically, the variant was identified in 1 internal prenatal sample referred for genetic testing with clinical indication of cystic hygroma and edema (Leach_2019) and it was confirmed to be de novo following parental testing. These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic.

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