Submissions for variant NM_001352514.2(HLCS):c.1439T>A (p.Val480Glu)

dbSNP: rs1198548955

Total submissions: 1

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001377994	SCV001575464	likely pathogenic	Holocarboxylase synthetase deficiency	2024-02-18	criteria provided, single submitter	clinical testing	This sequence change replaces valine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 333 of the HLCS protein (p.Val333Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with holocarboxylase synthetase deficiency (PMID: 10190325, 11735028; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1066875). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HLCS function (PMID: 10190325, 10590022). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.