Submissions for variant NM_006859.4(LIAS):c.218+1G>A

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV003643724	SCV004408794	likely pathogenic	Lipoic acid synthetase deficiency	2022-11-23	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the LIAS gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in LIAS are known to be pathogenic (PMID: 24334290, 27923773). This variant is present in population databases (rs779113995, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with LIAS-related conditions. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003643724	SCV005076205	likely pathogenic	Lipoic acid synthetase deficiency	2024-04-15	criteria provided, single submitter	clinical testing	Variant summary: LIAS c.218+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.3e-05 in 228068 control chromosomes (gnomAD). To our knowledge, no occurrence of c.218+1G>A in individuals affected with Pyruvate Dehydrogenase Lipoic Acid Synthetase Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 2814833). Based on the evidence outlined above, the variant was classified as likely pathogenic.