9-133352138-GCTCT-GCT

Variant names:

• chr9-133352138-GCT-G
• rs782007828
• NM_003172.4:c.754_755delAG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003172.4(SURF1):​c.754_755delAG​(p.Ser252HisfsTer39) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000438 in 1,597,582 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: SURF1 NM_003172.4 frameshift, splice_region
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.43
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• Leigh syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Labcorp Genetics (formerly Invitae)
• mitochondrial complex IV deficiency, nuclear type 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Charcot-Marie-Tooth disease type 4K

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Leigh syndrome with cardiomyopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Leigh syndrome with leukodystrophy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-133352138-GCT-G is Pathogenic according to our data. Variant chr9-133352138-GCT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 365526.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SURF1	NM_003172.4	c.754_755delAG	p.Ser252HisfsTer39	frameshift_variant, splice_region_variant	Exon 8 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.427_428delAG	p.Ser143HisfsTer39	frameshift_variant, splice_region_variant	Exon 7 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.754_755delAG	p.Ser252HisfsTer39	frameshift_variant, splice_region_variant	Exon 8 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.427_428delAG	p.Ser143HisfsTer39	frameshift_variant, splice_region_variant	Exon 7 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.664_665delAG		splice_region_variant, non_coding_transcript_exon_variant	Exon 7 of 8	5
SURF1	ENST00000495952.5	n.744_745delAG		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000454 AC: 1 AN: 220304 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000599

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000415 AC: 6 AN: 1445378 Hom.: 0 AF XY: 0.00000418 AC XY: 3 AN XY: 717380

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 42366

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25746

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39270

South Asian (SAS) AF: 0.00 AC: 0 AN: 83874

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51894

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5716

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1103408

Other (OTH) AF: 0.00 AC: 0 AN: 59808

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152204 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74338

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Pathogenic:3

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The SURF1 c.754_755delAG (p.Ser252HisfsTer39) variant, also known as c.752_753delAG, is a frameshift variant predicted to result in premature termination of the protein. The variant was first reported by Tanigawa et al. (2012) in a compound heterozygous state with a splice site variant in an individual with Leigh syndrome. Wedatilake et al. (2013) identified the c.754_755delAG variant in a homozygous state in one individual who had low muscle cytochrome c oxidase (COX) activity. Rodinová et al. (2014) described a third affected individual who was a compound heterozygote for the c.754_755delAG variant and another frameshift variant. The authors demonstrated that the amount and activity of complex IV (COX) in the fibroblasts of this patient was greatly reduced compared to that of healthy controls. Control data are unavailable for this variant, which is reported at a frequency of 0.00003 in the European (non-Finnish) population of the Exome Aggregation Consortium but this is from one allele in a region of low coverage. Based on the evidence from the literature and the potential impact of frameshift variants, the p.Ser252HisfsTer39 variant is interpreted as likely pathogenic for Leigh syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser252Hisfs*39) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 49 amino acid(s) of the SURF1 protein. This variant is present in population databases (rs782007828, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with mitochondrial complex IV deficiency (PMID: 22410471, 30872186). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.752_753del. ClinVar contains an entry for this variant (Variation ID: 365526). This variant disrupts a region of the SURF1 protein in which other variant(s) (p.Ser282Cysfs*9) have been determined to be pathogenic (PMID: 9837813, 16326995, 18583168, 22488715, 23829769). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Dec 06, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SURF1 c.754_755delAG (p.Ser252HisfsX39) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 4.5e-06 in 220304 control chromosomes. c.754_755delAG has been reported in the literature in multiple compound heterozygous and a homozygous individual affected with Leigh Syndrome (Tanigawa 2012, Wedatilake 2013, Rodinova 2014, Li 2018). These data indicate that the variant is likely to be associated with disease. Publications also reported that the variant results in low muscle cytochrome c oxidase (COX) activity in patients (Wedatilake 2013, Rodinova 2014). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The frameshift c.754_755del (p.Ser252HisfsTer39) variant has been reported in the literature in multiple compound heterozygous and a homozygous individual affected with Leigh Syndrome (Tanigawa J et al). This p.Ser252HisfsTer39 variant has allele frequency of 0.00045% in the gnomAD and novel (not in any individuals) in 1000 genome database. This variant has been reported to the ClinVar database as Pathogenic. This variant causes a frameshift starting with codon Serine 252, changes this amino acid to Histidine residue, and creates a premature Stop codon at position 39 of the new reading frame, denoted p.Ser252HisfsTer39. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic. -

Charcot-Marie-Tooth disease type 4K;C5435656:Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PM3_VeryStrong -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs782007828; hg19: chr9-136218993;