Submissions for variant NM_001098.3(ACO2):c.684+1G>T

gnomAD frequency: 0.00001  dbSNP: rs747330606

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000200546	SCV000251046	pathogenic	not provided	2024-11-08	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); Canonical splice site variant predicted to result in a null allele in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 34354088)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000200546	SCV002262469	likely pathogenic	not provided	2024-12-27	criteria provided, single submitter	clinical testing	This sequence change affects a donor splice site in intron 5 of the ACO2 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 ACO2 are known to be pathogenic (PMID: 30689204, 32519519). This variant is present in population databases (rs747330606, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with ACO2-related conditions. ClinVar contains an entry for this variant (Variation ID: 214017). 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	RCV004782301	SCV005395835	likely pathogenic	ACO2-related disorder	2024-09-17	criteria provided, single submitter	clinical testing	Variant summary: ACO2 c.684+1G>T 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing and loss of ACO2 function. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.2e-05 in 244348 control chromosomes. To our knowledge, no occurrence of c.684+1G>T in individuals affected with ACO2-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 214017). Based on the evidence outlined above, the variant was classified as likely pathogenic.