ClinVar Genomic variation as it relates to human health

Evaluation: The homozygous deletion of the 2 bases AG at position 136218825 on Chr 9 was is covered with 155 reads and is found in 90% of the reads. Both parents are heterozygous carriers of the deletion at this position (cover 101 Reads in the father and 45% of the reads show the deletion, 112 reads in the mother and 40% show the deletion). This variant leads to a shift of the reading frame from position 282 followed by a stop codon after nine amino acids. To bioinformatic prediction, this variant leads to the loss of function of SURF1 and is therefore classified as pathogenic. This variant is classified according to ACMG guidelines are also classified as pathogenic. Classification according to ACMG guidelines of c.845_846delCT: - PVS1: The variant leads to a loss of function of the gene or gene product . - PM2: The variant was only tested with a very low frequency in population genetic studies. (like GnomAD, Iranome, GME, 1kGP, etc.) identified, and not in homozygous state observed. - PM3: The variant is homozygous in a recessively inherited disease. - PP3: Bioinformatic prediction programs such as GERP and MutationTaster grade this variant as pathogenic. - PP5: In ClinVar this variant is classified as pathogenic: https://www.ncbi.nlm.nih.gov/ Clinvar/RCV000331329/ The SURF1 gene encodes part of the assembly factor of the mitochondrial complex IV (COX), which is found in of the inner mitochondrial membrane and is involved in the biogenesis of cytochrome C oxidase complex is involved. Mutations in SURF1 (MIM#185620) are observed in patients with the recessively inherited nuclear mitochondrial complexes IV deficiency, type 1 (MIM#220110), which has been clinically described as Leigh Syndrome can manifest. In a review by Wedatilake et al (2013), a patient (27) with developmental delay hypotension, poor food intake, failure to thrive (poor weight gain) and developmental regression and respiratory insufficiency, which has the same variant (c.845_846delCT) in compound heterozygosity with a splice mutation.

This variant was classified as: Pathogenic.

ACMG classification criteria: PVS1, PS4, PM3, PP1

This sequence change creates a premature translational stop signal (p.Ser282Cysfs*9) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the SURF1 protein. This variant is present in population databases (rs782316919, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive Leigh disease (PMID: 9837813, 16326995, 18583168, 22488715, 23829769). ClinVar contains an entry for this variant (Variation ID: 12770). For these reasons, this variant has been classified as Pathogenic.

Variant summary: The SURF1 c.845_846delCT (p.Ser282Cysfs) variant results in a premature termination codon, predicted to cause a truncated or absent SURF1 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in 19/120666 control chromosomes at a frequency of 0.0001575, which does not exceed the estimated maximal expected allele frequency of a pathogenic SURF1 variant (0.0017678). The variant has been reported in numerous affected individuals in the literature, both in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.010%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through protein truncation. Multiple pathogenic variants are reported in the predicted truncated region. It has been shared with similarly affected family member (3billion dataset). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 2 similarly affected unrelated individuals (PMID: 22488715). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.

Frameshift variant predicted to result in protein truncation, as the last 19 amino acids are replaced with 8 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 32020600, 23829769, 22488715, 29715184, 23408181, 16326995, 11317352, 26077850, 9837813, 18583168, 19780766, 31589614, 32709422, 34691145, 34490615)

The c.845_846delCT (p.S282Cfs*9) alteration, located in exon 9 (coding exon 9) of the SURF1 gene, consists of a deletion of 2 nucleotides from position 845 to 846, causing a translational frameshift with a predicted alternate stop codon after 9 amino acids. This alteration occurs at the 3' terminus of the SURF1 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 6% of the protein. However, premature stop codons are typically deleterious in nature (Ambry internal data). Based on data from gnomAD, the c.845_846delCT allele has an overall frequency of 0.010% (27/281946) total alleles studied. The highest observed frequency was 0.015% (19/128694) of European (non-Finnish) alleles. The c.845_856delCT deletion has been previously reported in multiple individuals with Leigh syndrome (Piekutowska-Abramczuk, 2009; Tiranti, 1998). Based on the available evidence, this alteration is classified as pathogenic.

SURF1: PM3:Very Strong, PM2, PVS1:Moderate

The SURF1 c.845_846delCT variant is predicted to result in a frameshift and premature protein termination (p.Ser282Cysfs*9). This variant, which is found at elevated frequencies in eastern European Slavic populations, has been reported in the compound heterozygous and homozygous states in many individuals with Leigh syndrome (Tiranti et al. 1998. PubMed ID: 9837813; Böhm et al. 2006. PubMed ID: 16326995; Lee et al. 2012. PubMed ID: 22488715; Lee et al. 2020. PubMed ID: 32020600; van der Ven et al. 2021. PubMed ID: 34490615; Kistol et al. 2023. PubMed ID: 36675121) and has been shown to co-segregate with disease in several affected families (Piekutowska-Abramczuk et al. 2009. PubMed ID: 19780766). Additionally, cultured fibroblasts and muscle cells from a homozygous individual were reported to only retain ~10% residual cytochrome oxidase activity (Tiranti et al. 1998. PubMed ID: 9837813). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in SURF1 are expected to be pathogenic. This variant is interpreted as pathogenic.