Submissions for variant NM_005356.5(LCK):c.1292C>T (p.Thr431Met)

gnomAD frequency: 0.00010  dbSNP: rs1801124

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001317326	SCV001507983	uncertain significance	Severe combined immunodeficiency due to LCK deficiency	2022-10-24	criteria provided, single submitter	clinical testing	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 431 of the LCK protein (p.Thr431Met). This variant is present in population databases (rs1801124, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with LCK-related conditions. ClinVar contains an entry for this variant (Variation ID: 1018077). 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 disruptive. 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.
Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	RCV001317326	SCV002495823	uncertain significance	Severe combined immunodeficiency due to LCK deficiency	2022-02-08	criteria provided, single submitter	clinical testing	This variant has not been reported in the literature but is present in 0.01% (9/68018) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/1-32280175-C-T?dataset=gnomad_r3). This variant is present in ClinVar (Variation ID:1018077). Evolutionary conservation for this variant is unclear; computational predictive tools suggest that this variant may not impact the protein. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.