NM_003172.4(SURF1):c.845_846del (p.Ser282fs) AND Leigh syndrome

Germline classification:: Pathogenic (4 submissions)
Last evaluated:: Jan 24, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

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:: RCV000331329.15

Allele description [Variation Report for NM_003172.4(SURF1):c.845_846del (p.Ser282fs)]

NM_003172.4(SURF1):c.845_846del (p.Ser282fs)

Gene:

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

Variant type:

Microsatellite

Cytogenetic location:

9q34.2

Genomic location:

Preferred name:

NM_003172.4(SURF1):c.845_846del (p.Ser282fs)

HGVS:

NC_000009.12:g.133351970AG[2]
NG_008477.1:g.9532CT[2]
NM_001280787.1:c.518_519del
NM_003172.4:c.845_846delMANE SELECT
NP_001267716.1:p.Ser173fs
NP_003163.1:p.Ser282fs
NC_000009.11:g.136218825AG[2]
NC_000009.11:g.136218825_136218826del
NM_003172.2:c.845_846delCT
NM_003172.3:c.845_846del
NM_003172.3:c.845_846delCT
NM_003172.4:c.845_846delCTMANE SELECT
p.S282Cfsx9
p.Ser282CysfsTer9

Protein change:

S173fs

Links:

OMIM: 185620.0004; OMIM: 185620.0014; dbSNP: rs782316919

NCBI 1000 Genomes Browser:

rs782316919

Molecular consequence:

NM_001280787.1:c.518_519del - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003172.4:c.845_846del - frameshift variant - [Sequence Ontology: SO:0001589]

Functional consequence:

functionally_abnormal [Sequence Ontology: SO:0002218]

Observations:

Condition(s)

Name:: Leigh syndrome (LS)
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
SCV000680396	Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Jan 12, 2018)	inherited, germline	clinical testing	Citation Link,
SCV000698184	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015)	Pathogenic (Oct 6, 2016)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 16326995, 18583168 LabCorp Variant Classification Summary - May 2015.docx, Citation Link,
SCV000752477	Invitae	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015))	Pathogenic (Jan 24, 2024)	germline	clinical testing	PubMed (6) [See all records that cite these PMIDs] 9837813, 16326995, 18583168, 22488715, 23829769, 28492532
SCV001370098	Centre for Mendelian Genomics, University Medical Centre Ljubljana	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Jan 1, 2016)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]

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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
not provided	inherited	yes	1	not provided	not provided	1	not provided	clinical testing
not provided	unknown	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	1	not provided	not provided	1	not provided	clinical testing

Citations

PubMed

Mutations of SURF-1 in Leigh disease associated with cytochrome c oxidase deficiency.

Tiranti V, Hoertnagel K, Carrozzo R, Galimberti C, Munaro M, Granatiero M, Zelante L, Gasparini P, Marzella R, Rocchi M, Bayona-Bafaluy MP, Enriquez JA, Uziel G, Bertini E, Dionisi-Vici C, Franco B, Meitinger T, Zeviani M.

Am J Hum Genet. 1998 Dec;63(6):1609-21.

PubMed [citation]

PMID:: 9837813
PMCID:: PMC1377632

Retrospective, multicentric study of 180 children with cytochrome C oxidase deficiency.

Böhm M, Pronicka E, Karczmarewicz E, Pronicki M, Piekutowska-Abramczuk D, Sykut-Cegielska J, Mierzewska H, Hansikova H, Vesela K, Tesarova M, Houstkova H, Houstek J, Zeman J.

Pediatr Res. 2006 Jan;59(1):21-6. Epub 2005 Dec 2.

PubMed [citation]

PMID:: 16326995

See all PubMed Citations (7)

Details of each submission

From Institute Of Human Genetics Munich, Klinikum Rechts Der Isar, Tu München, SCV000680396.2

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

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

From Women's Health and Genetics/Laboratory Corporation of America, LabCorp, SCV000698184.1

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

Description

Variant summary: The SURF1 c.845_846delCT (p.Ser282Cysfs) 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. One in silico tool predicts a damaging outcome for this variant. This variant was found in 19/120666 control chromosomes at a frequency of 0.0001575, which does not exceed the estimated maximal expected allele frequency of a pathogenic SURF1 variant (0.0017678). The variant has been reported in numerous affected individuals in the literature, both in the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as 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, SCV000752477.6

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (6)

Description

This sequence change creates a premature translational stop signal (p.Ser282Cysfs*9) in the SURF1 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 19 amino acid(s) of the SURF1 protein. This variant is present in population databases (rs782316919, gnomAD 0.02%). This premature translational stop signal has been observed in individuals with autosomal recessive Leigh disease (PMID: 9837813, 16326995, 18583168, 22488715, 23829769). ClinVar contains an entry for this variant (Variation ID: 12770). For these reasons, this variant has been classified as 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 Centre for Mendelian Genomics, University Medical Centre Ljubljana, SCV001370098.2

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

Description

This variant was classified as: Pathogenic.

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

Last Updated: Apr 15, 2024

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