Submissions for variant NM_005356.5(LCK):c.1515C>A (p.Tyr505Ter)

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center	RCV004785172	SCV005397766	likely pathogenic	Severe combined immunodeficiency due to LCK deficiency	2024-05-06	criteria provided, single submitter	clinical testing	This sequence variant is a single nucleotide substitution (C>A) at position 1515 of the coding sequence of the LCK gene that creates a premature termination signal at what would have been the Tyr505 codon. This variant is expected to generate a truncated protein lacking the final 6 amino acids. In particular, this variant will ablate the tyrosine at position 505 which is phosphorylated to contribute to the conformation and activity of the LCK-encoded LCK proto-oncogene, Src family tyrosine kinase. When phosphorylated, Tyr505 inactivates the LCK proto-oncogene, Src family tyrosine kinase by mediating the interaction of the amino and carboxyl terminals, which fold the protein into a closed state (PMID: 9325251, 28096507, 36910149). This is a novel variant which is absent from ClinVar, the gnomAD v4.1.0 population database (0 of 152,242 alleles), and, to the best of our knowledge, the clinical literature. While studies examining the functional consequence of this variant have not been published, LCK proteins which are phosphorylation-deficient remain in the open state and are subject to increased rates of degradation (PMID: 11904433). Based on these findings, we consider this a likely pathogenic variant. ACMG Criteria: PM2, PVS1