rs782316919

Positions:

• chr9-133351969-CAG-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_003172.4(SURF1):​c.845_846del​(p.Ser282CysfsTer9) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000936 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000094 (0 hom.)
• Consequence: SURF1 NM_003172.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18
• Conservation: PhyloP100: 1.05

Genes affected

SURF1 (HGNC:11474): (SURF1 cytochrome c oxidase assembly factor) This gene encodes a protein localized to the inner mitochondrial membrane and thought to be involved in the biogenesis of the cytochrome c oxidase complex. The protein is a member of the SURF1 family, which includes the related yeast protein SHY1 and rickettsial protein RP733. The gene is located in the surfeit gene cluster, a group of very tightly linked genes that do not share sequence similarity, where it shares a bidirectional promoter with SURF2 on the opposite strand. Defects in this gene are a cause of Leigh syndrome, a severe neurological disorder that is commonly associated with systemic cytochrome c oxidase deficiency. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0642 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-133351969-CAG-C is Pathogenic according to our data. Variant chr9-133351969-CAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 12770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133351969-CAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SURF1	NM_003172.4	c.845_846del	p.Ser282CysfsTer9	frameshift_variant	9/9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.518_519del	p.Ser173CysfsTer9	frameshift_variant	8/8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.845_846del	p.Ser282CysfsTer9	frameshift_variant	9/9	1	NM_003172.4	ENSP00000361042	P1
SURF1	ENST00000615505.4	c.518_519del	p.Ser173CysfsTer9	frameshift_variant	8/8	1		ENSP00000482067
SURF1	ENST00000437995.1	n.755_756del		non_coding_transcript_exon_variant	8/8	5
SURF1	ENST00000495952.5	n.835_836del		non_coding_transcript_exon_variant	5/5	2

Frequencies

GnomAD3 genomes AF: 0.0000854 AC: 13 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000998 AC: 25 AN: 250542 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135560

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000944 AC: 138 AN: 1461574 Hom.: 0 AF XY: 0.0000935 AC XY: 68 AN XY: 727050

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000854 AC: 13 AN: 152210 Hom.: 0 Cov.: 33 AF XY: 0.0000941 AC XY: 7 AN XY: 74358

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000529

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	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. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1998	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Genomic Statistics and Bioinformatics, University Hospital Bonn	-	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 04, 2021	- -

Leigh syndrome Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Jan 12, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 06, 2016	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	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. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 02, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2023	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) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	SURF1: PM3:Very Strong, PM2, PVS1:Moderate -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2022

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. -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Nov 16, 2020

ACMG classification criteria: PVS1, PS4, PM3, PP1 -

SURF1-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 29, 2023

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. -

Cerebellar ataxia;C0013362:Dysarthria;C0151786:Muscle weakness;C0234132:Abnormal pyramidal sign Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Leigh syndrome due to mitochondrial complex IV deficiency;C4225246:Charcot-Marie-Tooth disease type 4K Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 29, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs782316919; hg19: chr9-136218824;