NM_001686.4(ATP5F1B):c.1004T>C (p.Leu335Pro) AND Hypermetabolism due to Defect in Mitochondrial Coupling

Germline classification:: Pathogenic (1 submission)
Last evaluated:: Jul 29, 2022
Review status:: 1 star out of maximum of 4 stars
criteria provided, single submitter

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:: RCV003107982.3

Allele description [Variation Report for NM_001686.4(ATP5F1B):c.1004T>C (p.Leu335Pro)]

NM_001686.4(ATP5F1B):c.1004T>C (p.Leu335Pro)

Gene:

ATP5F1B:ATP synthase F1 subunit beta [Gene - OMIM - HGNC]

Variant type:

single nucleotide variant

Cytogenetic location:

12q13.3

Genomic location:

Preferred name:

NM_001686.4(ATP5F1B):c.1004T>C (p.Leu335Pro)

HGVS:

NC_000012.12:g.56642528A>G
NM_001686.4:c.1004T>CMANE SELECT
NP_001677.2:p.Leu335Pro
NC_000012.11:g.57036312A>G
NM_001686.3:c.1004T>C

Protein change:

L335P; LEU335PRO

Links:

OMIM: 102910.0001

Molecular consequence:

NM_001686.4:c.1004T>C - missense variant - [Sequence Ontology: SO:0001583]

Functional consequence:

gain_of_function_variant [Sequence Ontology: SO:0002053]

Observations:

Condition(s)

Name:: Hypermetabolism due to Defect in Mitochondrial Coupling
Identifiers:

Recent activity

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Caenorhabditis elegans Zmiz1 N-terminal tetratricopeptide repeat domain-containi...
Caenorhabditis elegans Zmiz1 N-terminal tetratricopeptide repeat domain-containing protein (miz-1), mRNA
gi|1845976252|ref|NM_001307057.4|

Nucleotide
Transcription initiation factor TFIID subunit 10 [Caenorhabditis elegans]
Transcription initiation factor TFIID subunit 10 [Caenorhabditis elegans]
gi|17562108|ref|NP_504260.1|

Protein

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV002555570	Ganetzky Laboratory, Children's Hospital of Philadelphia	criteria provided, single submitter (('ACMG 2015 criteria)	Pathogenic (Jul 29, 2022)	de novo, not applicable	clinical testing, research	Citation Link

Submission Accession

Submitter

Review Status
(Assertion method)

Clinical Significance
(Last evaluated)

Origin

Method

Citations

SCV002555570

Ganetzky Laboratory, Children's Hospital of Philadelphia

criteria provided, single submitter

(('ACMG 2015 criteria)

Pathogenic
(Jul 29, 2022)

de novo, not applicable

clinical testing, research

Citation Link

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Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	not applicable	not applicable	not provided	not provided	not provided	not provided	not provided	research
Ashkenazi Jewish	de novo	yes	1	not provided	not provided	not provided	not provided	clinical testing

Details of each submission

From Ganetzky Laboratory, Children's Hospital of Philadelphia, SCV002555570.1

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

Description

confirmed de novo variant in the affected twin boys. It is absent from controls and affects a highly evolutionarily conserved residue. Leu335 is in the critical hydrophobic sleeve region, where nearby mutations in yeast cause an uncoupling phenotype. Oxygen consumption and membrane potential studies in both patient fibroblasts and CRISPR-based knock in cells show loosened coupling within oxidative phosphorylation due to intrinsic complex V dysfunction. Further, heterologous expression of p.Leu335Pro on a wild-type background recapitulates these biochemical findings, consistent with a dominant-negative effect on coupling

Description

The Leu335Pro variant was confirmed de novo variant in affected monozygotic twins. It is absent from controls and affects a highly evolutionarily conserved residue. Leu335 is in the critical hydrophobic sleeve region, where nearby mutations in yeast cause an uncoupling phenotype. Oxygen consumption and membrane potential studies in both patient fibroblasts and CRISPR-based knock in cells show loosened coupling within oxidative phosphorylation due to intrinsic complex V dysfunction. Further, heterologous expression of p.Leu335Pro on a wild-type background recapitulates these biochemical findings, consistent with a dominant-negative effect on coupling. Based on these findings, the variant classified as “pathogenic” by American College of Medical Genetics and Genomics criteria based on de novo inheritance (PS2), in vitro functional studies (PS3), location in a critical region (PM1) and absence from controls (PM2)

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

Last Updated: Jun 23, 2024

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