NM_003172.4(SURF1):c.575G>A (p.Arg192Gln) AND Leigh syndrome

Germline classification:: Conflicting interpretations of pathogenicity (2 submissions)
Last evaluated:: Mar 29, 2022
Review status:: criteria provided, conflicting classifications

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV001797902.3

Allele description [Variation Report for NM_003172.4(SURF1):c.575G>A (p.Arg192Gln)]

NM_003172.4(SURF1):c.575G>A (p.Arg192Gln)

Gene:

SURF1:SURF1 cytochrome c oxidase assembly factor [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

9q34.2

Genomic location:

Preferred name:

NM_003172.4(SURF1):c.575G>A (p.Arg192Gln)

HGVS:

NC_000009.12:g.133352707C>T
NG_008477.1:g.8800G>A
NM_001280787.1:c.248G>A
NM_003172.4:c.575G>AMANE SELECT
NP_001267716.1:p.Arg83Gln
NP_003163.1:p.Arg192Gln
NC_000009.11:g.136219562C>T
NC_000009.11:g.136219562C>T
NM_003172.3:c.575G>A

Protein change:

R192Q

Links:

dbSNP: rs782021521

NCBI 1000 Genomes Browser:

rs782021521

Molecular consequence:

NM_001280787.1:c.248G>A - missense variant - [Sequence Ontology: SO:0001583]
NM_003172.4:c.575G>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:: Leigh syndrome (NULS)
Synonyms:: Leigh Disease; Subacute necrotizing encephalopathy; Necrotizing encephalopathy infantile subacute of Leigh; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0009723; MedGen: C0023264; Orphanet: 506; OMIM: 256000

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002041656	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Likely pathogenic (Nov 30, 2021)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 23829769, 30872186 Citation Link,
SCV003441400	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Uncertain significance (Mar 29, 2022)	germline	clinical testing	PubMed (7) [See all records that cite these PMIDs] 23829769, 30872186, 12515039, 19780766, 24027061, 27896082, 28492532

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002041656

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

criteria provided, single submitter

(LabCorp Variant Classification Summary - May 2015)

Likely pathogenic
(Nov 30, 2021)

germline

clinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link,

SCV003441400

Invitae

criteria provided, single submitter

(Invitae Variant Classification Sherloc (09022015))

Uncertain significance
(Mar 29, 2022)

germline

clinical testing

PubMed (7)
[See all records that cite these PMIDs]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SURF1 deficiency: a multi-centre natural history study.

Wedatilake Y, Brown RM, McFarland R, Yaplito-Lee J, Morris AA, Champion M, Jardine PE, Clarke A, Thorburn DR, Taylor RW, Land JM, Forrest K, Dobbie A, Simmons L, Aasheim ET, Ketteridge D, Hanrahan D, Chakrapani A, Brown GK, Rahman S.

Orphanet J Rare Dis. 2013 Jul 5;8:96. doi: 10.1186/1750-1172-8-96.

PubMed [citation]

PMID:: 23829769
PMCID:: PMC3706230

Panel-Based Nuclear and Mitochondrial Next-Generation Sequencing Outcomes of an Ethnically Diverse Pediatric Patient Cohort with Mitochondrial Disease.

Schoonen M, Smuts I, Louw R, Elson JL, van Dyk E, Jonck LM, Rodenburg RJT, van der Westhuizen FH.

J Mol Diagn. 2019 May;21(3):503-513. doi: 10.1016/j.jmoldx.2019.02.002. Epub 2019 Mar 11.

PubMed [citation]

PMID:: 30872186

See all PubMed Citations (7)

Details of each submission

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV002041656.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (2)

Description

Variant summary: SURF1 c.575G>A (p.Arg192Gln) results in a conservative amino acid change in the encoded protein sequence. Four 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.575G>A has been reported in the literature in two compound heterozygous individuals with mitochondrial complex IV deficiency, affected with Leigh Syndrome (Wedatilake_2013, Schoonen_2019). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Invitae, SCV003441400.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (7)

Description

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 192 of the SURF1 protein (p.Arg192Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of SURF1-related conditions (PMID: 23829769, 30872186). ClinVar contains an entry for this variant (Variation ID: 1329011). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant disrupts the p.Arg192 amino acid residue in SURF1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12515039, 19780766, 24027061, 27896082; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Jun 9, 2024

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