rs863224228

chr9-133354660-CGGCTGGCAGA-CAT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_003172.4(SURF1):c.312_321delinsAT(p.Leu105Ter) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. PL104H?) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SURF1 NM_003172.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 8.54

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 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-133354661-GGCTGGCAGA-AT is Pathogenic according to our data. Variant chr9-133354661-GGCTGGCAGA-AT is described in ClinVar as [Pathogenic]. Clinvar id is 215237.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SURF1	NM_003172.4	c.312_321delinsAT	p.Leu105Ter	frameshift_variant, splice_region_variant	4/9	ENST00000371974.8
SURF1	NM_001280787.1	c.-16_-7delinsAT		splice_region_variant, 5_prime_UTR_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SURF1	ENST00000371974.8	c.312_321delinsAT	p.Leu105Ter	frameshift_variant, splice_region_variant	4/9	1	NM_003172.4	P1
SURF1	ENST00000615505.4	c.-16_-7delinsAT		splice_region_variant, 5_prime_UTR_variant	3/8	1
SURF1	ENST00000437995.1	n.258_267delinsAT		splice_region_variant, non_coding_transcript_exon_variant	3/8	5

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 11, 2021	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22488715, 26257172, 23829769, 18804471, 29481804, 29715184, 32445240, 9837813) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	SURF1: PVS1, PM2, PM3, PS3:Supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Mar 08, 2021	PVS1, PS3 -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 27, 2021	PVS1, PS3, PM2, PS4_supporting -

Leigh syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 15, 2017	Variant summary: The SURF1 c.312_321delinsAT (p.Leu105Terfs) 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. p.Gln251X, c.758_759delCA, c.845_846delCT, etc.). This variant is absent in 121016 control chromosomes from ExAC. This variant is the most common pathogenic variant in Caucasian Leigh syndrome cohorts (Lee_2012, Wedatilake_2013, Lim_2014). Numerous patients carrying this variant in homozygous state as well as compound heterozygous state with other pathogenic/likely pathogenic variants have been identified, including reports of cosegregation in families carrying this variant. Biochemical enzymatic analysis in patient cells carrying this variant are show impaired enzymatic activity (Tiranti_1998, Lim_2014). In addition, multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Leu105*) in the SURF1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SURF1 are known to be pathogenic (PMID: 10443880, 22488715, 24027061). Information on the frequency of this variant in the gnomAD database is not available, as this variant may be reported differently in the database. This premature translational stop signal has been observed in individuals with Leigh syndrome (PMID: 9837813, 18804471, 23829769). This variant is also known as c.312_321del10insAT. ClinVar contains an entry for this variant (Variation ID: 215237). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Aug 18, 2015	This variant is predicted deleterious according to ACMG guidelines. Identified with another predicted deleterious variant, in an individual with Leigh syndrome and peripheral neuropathy. Parents were not available for segregation; however, given the similarity of the phenotypic presentation to that reported in the literature, it is likely that two variants in SURF1 are causing the phenotype in this individual. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2000

- -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 29, 2021

- -

SURF1-related condition Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 30, 2023

The SURF1 c.312_321delinsAT variant is predicted to result in premature protein termination (p.Leu105*). This variant has previously been reported to be causative for Leigh syndrome due to cytochrome c oxidase (COX) deficiency (e.g., Tiranti et al. 1998. PubMed ID: 9837813; Marsy et al. 2008. PubMed ID: 18804471; Martin-Saavedra et al. 2021. PubMed ID: 34052969). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in SURF1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs863224228; hg19: chr9-136221516;