Submissions for variant NM_003172.4(SURF1):c.752-1G>C

gnomAD frequency: 0.00001  dbSNP: rs1391748504

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV000578241	SCV000680397	pathogenic	Leigh syndrome	2017-11-03	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000578241	SCV001361832	pathogenic	Leigh syndrome	2022-12-27	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.752-1G>C 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: five predict the variant abolishes a 3' acceptor site, and four predict the variant creates a 3' acceptor site two nucleotides downstream of the original 3' acceptor site (which would result in a frame-shift at the protein level). However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 9.2e-06 in 216730 control chromosomes (gnomAD). c.752-1G>C has been reported in the literature in multiple individuals affected with Leigh Syndrome (e.g. Pieutowska-Abramczuk_2009, Katkevica_2021). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000578241	SCV004295599	pathogenic	Leigh syndrome	2024-08-30	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 7 of the SURF1 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 SURF1 are known to be pathogenic (PMID: 10443880, 22488715, 24027061). This variant is present in population databases (no rsID available, gnomAD 0.003%). Disruption of this splice site has been observed in individual(s) with Leigh syndrome (PMID: 18583168, 34868319). 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: 488613). 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.
GeneDx	RCV004592782	SCV005081150	pathogenic	not provided	2023-06-27	criteria provided, single submitter	clinical testing	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; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 36675121, 18583168, 34868319)