rs121918657

Positions:

• chr9-133352446-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003172.4(SURF1):​c.751C>T​(p.Gln251*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000109 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: SURF1 NM_003172.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.001880
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: -1.01

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 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 9-133352446-G-A is Pathogenic according to our data. Variant chr9-133352446-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 12762.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133352446-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SURF1	NM_003172.4	c.751C>T	p.Gln251*	stop_gained, splice_region_variant	7/9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1	c.424C>T	p.Gln142*	stop_gained, splice_region_variant	6/8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SURF1	ENST00000371974.8	c.751C>T	p.Gln251*	stop_gained, splice_region_variant	7/9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4	c.424C>T	p.Gln142*	stop_gained, splice_region_variant	6/8	1		ENSP00000482067.1
SURF1	ENST00000437995.1	n.661C>T		splice_region_variant, non_coding_transcript_exon_variant	6/8	5
SURF1	ENST00000495952.5	n.741C>T		splice_region_variant, non_coding_transcript_exon_variant	3/5	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251466 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135918

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461874 Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Leigh syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2023	This sequence change creates a premature translational stop signal (p.Gln251*) 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). This variant is present in population databases (rs121918657, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of SURF1-related conditions (PMID: 9837813, 28639102, 32445240). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 12762). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 10, 2016	Variant summary: The c.751C>T variant results in a premature termination codon, predicted to cause a truncated or absent SURF1 protein, which is a commonly known mechanism for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g.c.758_759delCA/p.Thr253fsX38). One in-silico tool predicts damaging outcome for this variant. This variant is found in 1/121348 control chromosomes at a frequency of 0.0000082, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0017678). This variant has been reported in 5 LS patients in homozygous or compound heterozygous state. Furthermore, independent studies showed that cells derived from patients have been shown to have reduced COX activity. Additionally, multiple reputable databases classified this variant as pathogenic. Taken together, this variant was classified as pathogenic. -

Mitochondrial complex IV deficiency, nuclear type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1998

- -

Mitochondrial disease Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 16, 2023

The SURF1 c.751C>T (p.Gln251Ter) nonsense variant results in the premature termination of the protein at amino acid position 251. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant has been reported several times in the literature including in a homozygous or compound heterozygous state (PMID: 9837813; PMID: 23829769; PMID: 34302356). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000012 in the Total population (version 2.1.1). This variant was identified in trans with a pathogenic variant. Based on the available evidence, the c.751C>T (p.Gln251Ter) variant is classified as pathogenic for primary mitochondrial disorder. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2018

The Q251X variant has been published in association with Leigh syndrome associated with cytochrome c oxidase deficiency (Tiranti et al. 1998). The Q251X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. In summary, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Benign	0.87
Eigen	Benign	-0.55
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.62	D
Vest4		0.75
GERP RS		-10

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.22
SpliceAI score (max)		0.070		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: rs121918657; hg19: chr9-136219301; COSMIC: COSV59299468; COSMIC: COSV59299468;