rs782190413

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_003172.4(SURF1):c.574C>T(p.Arg192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,262 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192Q) has been classified as Likely pathogenic.

Frequency

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

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

SURF1
NM_003172.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 0.659

Publications

9 publications found

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 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

SURF1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 19 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_003172.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-133352707-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1329011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 15 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: -0.68006 (below the threshold of 3.09). Trascript score misZ: -1.3185 (below the threshold of 3.09). GenCC associations: The gene is linked to Leigh syndrome with leukodystrophy, Leigh syndrome, mitochondrial complex IV deficiency, nuclear type 1, Charcot-Marie-Tooth disease type 4K, Leigh syndrome with cardiomyopathy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.965

PP5

Variant 9-133352708-G-A is Pathogenic according to our data. Variant chr9-133352708-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 215235.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 link	c.574C>T	p.Arg192Trp	missense_variant	Exon 6 of 9	ENST00000371974.8	NP_003163.1
SURF1	NM_001280787.1 link	c.247C>T	p.Arg83Trp	missense_variant	Exon 5 of 8		NP_001267716.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SURF1	ENST00000371974.8 link	c.574C>T	p.Arg192Trp	missense_variant	Exon 6 of 9	1	NM_003172.4	ENSP00000361042.3
SURF1	ENST00000615505.4 link	c.247C>T	p.Arg83Trp	missense_variant	Exon 5 of 8	1		ENSP00000482067.1
SURF1	ENST00000437995.1 link	n.484C>T		non_coding_transcript_exon_variant	Exon 5 of 8	5
SURF1	ENST00000495952.5 link	n.564C>T		non_coding_transcript_exon_variant	Exon 2 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000120

AC:

AN:

249494

AF XY:

0.00000740

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461090

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.0000897

AC:

AN:

33462

American (AMR)

AF:

0.00

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5550

European-Non Finnish (NFE)

AF:

0.00000899

AC:

AN:

1111792

Other (OTH)

AF:

0.0000166

AC:

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000965

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68012

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000491

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Leigh syndrome

Pathogenic:2

Apr 13, 2023

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.574C>T (p.Arg192Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 249494 control chromosomes (gnomAD). c.574C>T has been reported in the literature in the compound heterozygous state in multiple individuals affected with Leigh Syndrome, including at least one case where it was confirmed to be in trans with a pathogenic variant (e.g Pecina_2003, Piekutowska-Abramczuk_2009, Echaniz-Laguna_2013, Wedatilake_2013, Shimbo_2014). These data indicate that the variant is likely to be associated with disease. Assessment of fibroblast mitochondria from a compound heterozygous patient with the variant (c.574C>T/c.841delCT) showed undetectable Surf1 protein levels and COX activity approximately 20% of normal (Pecina_2003). Additionally, another variant affecting the same amino acid, p.Arg192Gln, has been observed in affected individuals and classified as likely pathogenic by our laboratory, suggesting Arg192 may be important for protein function. Four submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic (n=3)/likely pathogenic (n=1). Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 192 of the SURF1 protein (p.Arg192Trp). This variant is present in population databases (rs782190413, gnomAD 0.01%). This missense change has been observed in individual(s) with Charcot-Marie-Tooth disease, type 4 (CMT4) or Leigh syndrome (PMID: 12515039, 19780766, 24027061, 27896082). 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: 215235). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt SURF1 protein function with a positive predictive value of 95%. This variant disrupts the p.Arg192 amino acid residue in SURF1. Other variant(s) that disrupt this residue have been observed in individuals with SURF1-related conditions (PMID: 16542579, 23829769), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

May 09, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 12515039, 24027061, 27896082, 19780766, 23829769, 16542579, 12943968, 31589614) -

May 28, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mitochondrial disease

Pathogenic:1

Feb 16, 2023

Illumina Laboratory Services, Illumina

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The SURF1 c.574C>T (p.Arg192Trp) missense variant results in the substitution of arginine at amino acid position 192 with tryptophan. This variant has been reported in at least five individuals with primary mitochondrial disease, in trans with another SURF1 variant (PMID: 19780766; PMID: 23829769; PMID: 24027061; PMID: 27896082). This variant is reported in the Genome Aggregation Database in three alleles at a frequency of 0.000121 in the African/African-American population (version 2.1.1). Multiple lines of computational evidence suggest the variant may have a deleterious effect on the gene or gene product. This variant was identified in trans with a pathogenic variant. Based on the available evidence, the c.574C>T (p.Arg192Trp) variant is classified as pathogenic for primary mitochondrial disease. -

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

Pathogenic:1

Mar 13, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Charcot-Marie-Tooth disease type 4K

Pathogenic:1

Oct 22, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.54

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.98

D;.

Eigen

Benign

-0.049

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.91

M_CAP

Pathogenic

0.59

MetaRNN

Pathogenic

0.96

D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.6

H;.

PhyloP100

0.66

PrimateAI

Uncertain

0.51

PROVEAN

Pathogenic

-7.3

D;.

REVEL

Pathogenic

0.77

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;.

Vest4

0.71

MVP

0.95

MPC

0.20

ClinPred

0.95

GERP RS

-0.47

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.92

gMVP

0.89

Mutation Taster

=18/82

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

Splicevardb

2.0

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over