NM_003172.4(SURF1):c.574_575insCTGC (p.Arg192fs) AND Mitochondrial complex IV deficiency, nuclear type 1

Germline classification:: Pathogenic (2 submissions)
Last evaluated:: Feb 2, 2022
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:: RCV002272252.5

Allele description [Variation Report for NM_003172.4(SURF1):c.574_575insCTGC (p.Arg192fs)]

NM_003172.4(SURF1):c.574_575insCTGC (p.Arg192fs)

Gene:

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

Variant type:

Insertion

Cytogenetic location:

9q34.2

Genomic location:

Preferred name:

NM_003172.4(SURF1):c.574_575insCTGC (p.Arg192fs)

HGVS:

NC_000009.12:g.133352708_133352709insCAGG
NG_008477.1:g.8799_8800insCTGC
NM_001280787.1:c.247_248insCTGC
NM_003172.4:c.574_575insCTGCMANE SELECT
NP_001267716.1:p.Arg83fs
NP_003163.1:p.Arg192fs
NC_000009.11:g.136219562_136219563insGCAG
NC_000009.11:g.136219563_136219564insCAGG
NM_003172.2:c.574_575insCTGC
NM_003172.3:c.574_575insCTGC
p.Arg192Profs*8

Protein change:

R192fs

Links:

dbSNP: rs782289759

NCBI 1000 Genomes Browser:

rs782289759

Molecular consequence:

NM_001280787.1:c.247_248insCTGC - frameshift variant - [Sequence Ontology: SO:0001589]
NM_003172.4:c.574_575insCTGC - frameshift variant - [Sequence Ontology: SO:0001589]

Observations:

Condition(s)

Name:: Mitochondrial complex IV deficiency, nuclear type 1
Synonyms:: Mitochondrial complex IV deficiency; Complex 4 mitochondrial respiratory chain deficiency; Deficiency of mitochondrial respiratory chain complex4; See all synonyms [MedGen]
Identifiers:: MONDO: MONDO:0700250; MedGen: C5435656; OMIM: 220110

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002557718	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute See additional submitters Shariant Australia, Australian Genomics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Feb 2, 2022)	germline	clinical testing	PubMed (2) [See all records that cite these PMIDs] 22488715, 25741868
SCV002764919	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	criteria provided, single submitter (Classification criteria August 2017)	Pathogenic (Mar 4, 2021)	maternal	clinical testing	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002557718

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

See additional submitters

criteria provided, single submitter

(ACMG Guidelines, 2015)

Pathogenic
(Feb 2, 2022)

germline

clinical testing

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

SCV002764919

Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München

criteria provided, single submitter

(Classification criteria August 2017)

Pathogenic
(Mar 4, 2021)

maternal

clinical testing

Citation Link

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	maternal	yes	1	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

SURF1-associated Leigh syndrome: a case series and novel mutations.

Lee IC, El-Hattab AW, Wang J, Li FY, Weng SW, Craigen WJ, Wong LJ.

Hum Mutat. 2012 Aug;33(8):1192-200. doi: 10.1002/humu.22095. Epub 2012 Apr 30.

PubMed [citation]

PMID:: 22488715

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL; ACMG Laboratory Quality Assurance Committee..

Genet Med. 2015 May;17(5):405-24. doi: 10.1038/gim.2015.30. Epub 2015 Mar 5.

PubMed [citation]

PMID:: 25741868
PMCID:: PMC4544753

Details of each submission

From Victorian Clinical Genetics Services, Murdoch Childrens Research Institute, SCV002557718.1

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

Description

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with mitochondrial complex IV deficiency, nuclear type 1 (MIM#220110) and Charcot-Marie-Tooth disease, type 4K (MIM#616684). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (12 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. These variants have been reported many times as pathogenic (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic or likely pathogenic, and has been observed in multiple individuals with Leigh syndrome (ClinVar, PMID: 22488715). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

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

From Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München, SCV002764919.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	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	maternal	yes	not provided	not provided	not provided		1	not provided	not provided	not provided

Last Updated: Apr 20, 2024

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