Submissions for variant NM_024884.3(L2HGDH):c.256+1G>A

gnomAD frequency: 0.00001  dbSNP: rs150299874

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000438376	SCV000517201	pathogenic	not provided	2015-05-12	criteria provided, single submitter	clinical testing	The c.256+1G>A variant in the L2HGDH gene has not been reported previously as a pathogenic variant nor as a benign polymorphism, to our knowledge. This splice site variant destroys the canonicalsplice donor site in intron 2. It is predicted to cause abnormal gene splicing, either leading to an abnormalmessage that is subject to nonsense-mediated mRNA decay, or to an abnormal protein product if themessage is used for protein translation. The c.256+1G>A substitution was not observed at any significantfrequent in approximately 6,500 individuals of European and African American ancestry in the NHLBIExome Sequencing Project, indicating it is not a common benign variant in these populations. We interpretc.256+1G>A as a pathogenic variant.
Fulgent Genetics, Fulgent Genetics	RCV000763339	SCV000894021	pathogenic	L-2-hydroxyglutaric aciduria	2021-11-16	criteria provided, single submitter	clinical testing
Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	RCV000763339	SCV001134999	pathogenic	L-2-hydroxyglutaric aciduria	2019-11-05	criteria provided, single submitter	clinical testing	A homozygous 5' splice site variation in intron 2 of the L2HGDH gene that affects the invariant GT donor splice site of exon 2 was detected. The observed variant has not been reported in the 1000 genomes and has a minor allele frequency of 0.002% in the ExAC databases. The in silico prediction of the variant is damaging by MutationTaster2. The reference codon is conserved across species. In summary, c.256+1G>A variant meets our criteria to be classified as a pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000763339	SCV002500715	likely pathogenic	L-2-hydroxyglutaric aciduria	2022-03-28	criteria provided, single submitter	clinical testing	Variant summary: L2HGDH c.256+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 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 251428 control chromosomes (gnomAD). c.256+1G>A has been reported in the literature in a homozygous individual affected with L-2 Aciduria (Shah-2020). Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic.
Invitae	RCV000763339	SCV003269018	pathogenic	L-2-hydroxyglutaric aciduria	2022-09-13	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 2 of the L2HGDH 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 L2HGDH are known to be pathogenic (PMID: 16134148, 20052767). This variant is present in population databases (rs150299874, gnomAD 0.01%). Disruption of this splice site has been observed in individuals with L-2-hydroxyglutaric aciduria (PMID: 32626804; Invitae). ClinVar contains an entry for this variant (Variation ID: 379781). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.