Submissions for variant NM_004744.5(LRAT):c.459dup (p.Tyr154fs)

dbSNP: rs765063151

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000598854	SCV000710265	likely pathogenic	not provided	2018-01-03	criteria provided, single submitter	clinical testing	The c.459dupC variant in the LRAT gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.459dupC variant causes a frameshift starting with codon Tyrosine 154, changes this amino acid to a Leucine residue, and creates a premature Stop codon at position 30 of the new reading frame, denoted p.Tyr154LeufsX30. This variant is predicted to cause loss of normal protein function through protein truncation as the last 77 amino acids of the protein are lost and replaced with 29 incorrect amino acids. The c.459dupC variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.459dupC as a likely pathogenic variant.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000598854	SCV001202408	pathogenic	not provided	2023-11-21	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Tyr154Leufs*30) in the LRAT gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 77 amino acid(s) of the LRAT protein. This variant is present in population databases (rs765063151, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with LRAT-related conditions. ClinVar contains an entry for this variant (Variation ID: 503963). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant disrupts a region of the LRAT protein in which other variant(s) (p.Ile174Serfs*12) have been determined to be pathogenic (PMID: 21217109). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.