Submissions for variant NM_003172.4(SURF1):c.324-11T>G

dbSNP: rs375398247

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000198496	SCV000252349	pathogenic	not provided	2023-05-24	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 30283815, 35693685, 27475922, 34220073, 22488715, 34302356, 23829769)
Revvity Omics, Revvity	RCV000198496	SCV003818150	uncertain significance	not provided	2019-02-26	criteria provided, single submitter	clinical testing
3billion, Medical Genetics	RCV003152693	SCV003841513	uncertain significance	Mitochondrial complex IV deficiency, nuclear type 1	2023-02-23	criteria provided, single submitter	clinical testing	This intron variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tools predict the variant to alter splicing and produce an abnormal transcript (SpliceAI: 0.96). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22488715). The variant has been reported to be associated with SURF1-related disorder (ClinVar ID: VCV000215232). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Lifecell International Pvt. Ltd	RCV003152693	SCV003845978	pathogenic	Mitochondrial complex IV deficiency, nuclear type 1		criteria provided, single submitter	clinical testing	A Homozygote Intron variant c.324-11T>G in Exon 4 of the SURF1 gene that results in the amino acid substitution was identified. The observed variant has a minor allele frequency of 0.00002/0% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is high, based on the effect of the protein and REVEL score . Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. ClinVar has also classified this variant as Pathogenic (Variant ID: 215232). This variant has been reported in association with atypical Leigh syndrome (Wedatilake Y et al., 2013 and Finsterer J et al., 2022). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines.
Labcorp Genetics (formerly Invitae), Labcorp	RCV003509513	SCV004295603	pathogenic	Leigh syndrome	2024-11-24	criteria provided, single submitter	clinical testing	This sequence change falls in intron 4 of the SURF1 gene. It does not directly change the encoded amino acid sequence of the SURF1 protein. This variant is present in population databases (rs375398247, gnomAD 0.01%). This variant has been observed in individuals with clinical features of Leigh syndrome due to mitochondrial complex IV deficiency (PMID: 22488715, 23829769). ClinVar contains an entry for this variant (Variation ID: 215232). 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.
Kasturba Medical College, Manipal, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, India	RCV003152693	SCV005081687	uncertain significance	Mitochondrial complex IV deficiency, nuclear type 1		criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003509513	SCV005394361	pathogenic	Leigh syndrome	2024-09-30	criteria provided, single submitter	clinical testing	Variant summary: SURF1 c.324-11T>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant abolishes a 3' acceptor site. One predict the variant weakens a 3' acceptor site. Three predict the variant creates a 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 1.6e-05 in 251118 control chromosomes. c.324-11T>G has been reported in the literature in multiple individuals affected with Leigh Syndrome (e.g. Wedatilake_2013, Lee_2012). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 22488715, 23829769). ClinVar contains an entry for this variant (Variation ID: 215232). Based on the evidence outlined above, the variant was classified as pathogenic.