Submissions for variant NM_005921.2(MAP3K1):c.458C>T (p.Pro153Leu)

dbSNP: rs576080629

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Genetic Services Laboratory, University of Chicago	RCV000500033	SCV000595699	likely benign	not specified	2017-01-05	criteria provided, single submitter	clinical testing
GeneDx	RCV000657924	SCV000779691	uncertain significance	not provided	2018-05-16	criteria provided, single submitter	clinical testing	The P153L variant in the MAP3K1 gene has been reported previously in an individual with abnormal gonadal development with no further clinical details provided (Loke et al., 2014). Functional studies of this variant demonstrated altered binding of protein co-factors and increased phosphorylation of downstream targets, suggesting a possible gain of function (Loke et al., 2014). However, the clinical validity of these functional studies is unknown (Bashamboo et al., 2015). The P153L variant is not observed in large population cohorts (Lek et al., 2016). The P153L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, in-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. We interpret P153L as a variant of uncertain significance.
Invitae	RCV003525915	SCV004309847	uncertain significance	46,XY sex reversal 6	2023-06-30	criteria provided, single submitter	clinical testing	This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects MAP3K1 function (PMID: 24135036, 30608580). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt MAP3K1 protein function. ClinVar contains an entry for this variant (Variation ID: 435820). This missense change has been observed in individuals with gonadal dysplasia (PMID: 24135036; Invitae). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 153 of the MAP3K1 protein (p.Pro153Leu).