rs782190413

Positions:

chr9-133352708-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_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 (★★).

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

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:

SURF1 (HGNC:):

SURF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1

In a chain Surfeit locus protein 1 (size 299) in uniprot entity SURF1_HUMAN there are 17 pathogenic changes around while only 2 benign (89%) in NM_003172.4

PM2

Very rare variant in population databases, with high coverage;

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 [Likely_pathogenic]. Clinvar id is 215235.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-133352708-G-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.574C>T	p.Arg192Trp	missense_variant	6/9	ENST00000371974.8	NP_003163.1	Q15526-1E5KRX5
SURF1	NM_001280787.1 linkuse as main transcript	c.247C>T	p.Arg83Trp	missense_variant	5/8		NP_001267716.1	Q15526A0A087WYS9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SURF1	ENST00000371974.8 linkuse as main transcript	c.574C>T	p.Arg192Trp	missense_variant	6/9	1	NM_003172.4	ENSP00000361042.3	Q15526-1
SURF1	ENST00000615505.4 linkuse as main transcript	c.247C>T	p.Arg83Trp	missense_variant	5/8	1		ENSP00000482067.1	A0A087WYS9
SURF1	ENST00000437995.1 linkuse as main transcript	n.484C>T		non_coding_transcript_exon_variant	5/8	5
SURF1	ENST00000495952.5 linkuse as main transcript	n.564C>T		non_coding_transcript_exon_variant	2/5	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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249494

Hom.:

AF XY:

0.00000740

AC XY:

AN XY:

135060

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 SAS exome

AF:

0.0000329

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

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152172

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 13, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2024	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SURF1 protein function with a positive predictive value of 80%. 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

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 28, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2023	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) -

Mitochondrial disease

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Feb 16, 2023

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 13, 2024

- -

Charcot-Marie-Tooth disease type 4K

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 22, 2013

- -

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

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;.

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

Splicing

Name

Calibrated prediction

Score

Prediction

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

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