9-133352100-ACT-A

Position:

chr9-133352100-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_003172.4(SURF1):c.792_793del(p.Arg264SerfsTer27) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000205 in 1,609,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

SURF1
NM_003172.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 5.63

Variant links:

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]

SURF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.123 CDS is truncated, and there are 3 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-133352100-ACT-A is Pathogenic according to our data. Variant chr9-133352100-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 215238.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133352100-ACT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SURF1	NM_003172.4 linkuse as main transcript	c.792_793del	p.Arg264SerfsTer27	frameshift_variant	8/9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1 linkuse as main transcript	c.465_466del	p.Arg155SerfsTer27	frameshift_variant	7/8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8 linkuse as main transcript	c.792_793del	p.Arg264SerfsTer27	frameshift_variant	8/9	1	NM_003172.4	ENSP00000361042	P1	Q15526-1
SURF1	ENST00000615505.4 linkuse as main transcript	c.465_466del	p.Arg155SerfsTer27	frameshift_variant	7/8	1		ENSP00000482067
SURF1	ENST00000437995.1 linkuse as main transcript	n.702_703del		non_coding_transcript_exon_variant	7/8	5
SURF1	ENST00000495952.5 linkuse as main transcript	n.782_783del		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000417

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000165

AC:

AN:

242498

Hom.:

AF XY:

0.00000763

AC XY:

AN XY:

131068

show subpopulations

Gnomad AFR exome

AF:

0.0000655

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000340

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000167

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1457572

Hom.:

AF XY:

0.0000235

AC XY:

AN XY:

724552

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000227

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000820

Gnomad4 FIN exome

AF:

0.0000189

Gnomad4 NFE exome

AF:

0.0000135

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151912

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000417

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Mitochondrial complex IV deficiency, nuclear type 1

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The frameshift variant c.792_793del(p.Arg264SerfsTer27) in SURF1 gene has been reported in several individuals and families affected with cytochrome c oxidase (COX) deficient Leigh syndrome (Lim SC et.al.,2014). This variant has been reported to the ClinVar database as Pathogenic. The p.Arg264SerfsTer27 variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.002191% is reported in gnomAD. This variant causes a frameshift starting with codon Arginine 264, changes this amino acid to Serine residue, and creates a premature Stop codon at position 27 of the new reading frame, denoted p.Arg264SerfsTer27. For these reasons, this variant has been classified as Pathogenic -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	May 06, 2020	Across a selection of the available literature, the SURF1 c.792_793delAG (p.Arg264SerfsTer27) variant, a frameshift variant, has been identified in at least seven unrelated individuals with Leigh syndrome, including in four in a homozygous state and three in a compound heterozygous state (Wedatilake et al. 2013; Sonam et al. 2017; Li et al. 2018). Clinical features of the probands included onset in infancy with poor feeding, vomiting, developmental regression, nystagmus, ophthalmoplegia, hypotonia, movement disorder, and respiratory failure (Wedatilake et al. 2013; Li et al. 2018). Fibroblast COX activity from two patients showed significantly reduced activity and COX histochemistry demonstrated reduced COX staining in muscle biopsies from four patients (Wedatilake et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.000022 in the Total population of the Genome Aggregation Database. Based on the collective evidence and application of the ACMG criteria, the c.792_793delAG (p.Arg264SerfsTer27) variant is classified as pathogenic for Mitochondrial complex IV deficiency. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 01, 2001	- -

Leigh syndrome

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	3billion	Oct 02, 2021	Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000219, PM2). The variant has been reported as pathogenic (ClinVar ID: SCV000033851). Patient's phenotype is considered compatible with Leigh syndrome, due to COX IV deficiency (3billion dataset, PP4). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 10, 2017	Variant summary: The SURF1 c.792_793delAG (p.Arg264Serfs) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.845_846delCT, p.Ser282fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 1/83140 control chromosomes at a frequency of 0.000012, which does not exceed the estimated maximal expected allele frequency of a pathogenic SURF1 variant (0.0017678). The variant was reported in the literature in numerous affected individuals, and two homozygous patients tested for fibroblast COX activity showed significantly reduced activity (Wedatilake_2013). 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	Dec 16, 2023	This sequence change creates a premature translational stop signal (p.Arg264Serfs27) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 37 amino acid(s) of the SURF1 protein. This variant is present in population databases (rs782490558, gnomAD 0.007%). This premature translational stop signal has been observed in individuals with cytochrome c oxidase (COX) deficient Leigh syndrome (PMID: 10647889, 23829769, 24462369). ClinVar contains an entry for this variant (Variation ID: 215238). This variant disrupts the p.Lys291 amino acid residue in SURF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9837813, 25111564, 27756633). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Jan 01, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 01, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 2023	Reported in two patients with Leigh syndrome who harbored different frameshift variants on the opposite allele (in trans) (PMID: 28639102); Frameshift variant predicted to result in protein truncation, as the last 37 amino acids are replaced with 26 different amino acids, and other loss-of-function variants have been reported downstream in the Human Gene Mutation Database (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24462369, 10647889, 23829769, 26762927, 11409433, 31589614, 32907636, 36675121, 31965297, 33594065, 28639102) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 02, 2021

The c.792_793delAG (p.R264Sfs*27) alteration, located in exon 8 (coding exon 8) of the SURF1 gene, consists of a deletion of 2 nucleotides from position 792 to 793, causing a translational frameshift with a predicted alternate stop codon after 27 amino acids. This alteration occurs at the 3' terminus of the SURF1 gene and is not expected to trigger nonsense-mediated mRNA decay; however, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). Based on data from gnomAD, the c.792_793delAG allele has an overall frequency of <0.01% (6/273842) total alleles studied. The highest observed frequency was 0.01% (1/7068) of Other alleles. This mutation has been identified in the homozygous and compound heterozygous state in multiple individuals with SURF1-related mitochondrial complex IV deficiency (Péquignot, 2001; Wedatilake, 2013; Li, 2018; Tsang, 2020). Other truncating alterations downstream have been observed in individuals with a personal and/or family history that is consistent with SURF1-related mitochondrial complex IV deficiency (Tiranti, 1998; Piekutowska-Abramczuk, 2009). Based on the available evidence, this alteration is classified as pathogenic. -

Charcot-Marie-Tooth disease type 4K

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

DASA

Jan 05, 2022

The c.792_793del;p.(Arg264Serfs*27) is a null frameshift variant (NMD) in the SURF1 gene and predicts alteration of the nonsense-mediate decay - NMD is present in a relevantexon to the transcript - PVS1_strong. This sequence change has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 215238; PMID: 10647889;23829769; 24462369; 26341968) - PS4. The variant is present at low allele frequencies population databases (rs782490558– gnomAD 0.003291%; ABraOM 0.000427 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Arg264Serfs*27) was detected in trans with a pathogenic variant (PMID: 28639102) - PM3. In summary, the currently available evidence indicates that the variant is pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over