VCV000209179.22 - ClinVar

NM_025152.3(NUBPL):c.311T>C (p.Leu104Pro)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic/Likely pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_025152.3(NUBPL):c.311T>C (p.Leu104Pro)

Variation ID: 209179 Accession: VCV000209179.22

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 14q12 14: 31599308 (GRCh38) [ NCBI UCSC ] 14: 32068514 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Sep 29, 2015	Dec 28, 2024	Dec 16, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_025152.3:c.311T>C MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_079428.2:p.Leu104Pro	missense
NM_001201573.2:c.23T>C	NP_001188502.1:p.Leu8Pro	missense
NR_120408.2:n.347T>C		non-coding transcript variant
NC_000014.9:g.31599308T>C
NC_000014.8:g.32068514T>C
NG_028349.1:g.42924T>C

... more HGVS ... less HGVS

Protein change

L104P, L8P

Other names

p.Leu104Pro

Canonical SPDI

NC_000014.9:31599307:T:C

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Decreased function

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD) 0.00006

Trans-Omics for Precision Medicine (TOPMed) 0.00006

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008

The Genome Aggregation Database (gnomAD), exomes 0.00015

Exome Aggregation Consortium (ExAC) 0.00021

Links

ClinGen: CA250383 OMIM: 613621.0009 dbSNP: rs201430951 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
NUBPL		-	-	GRCh38 GRCh37	269	310

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Mitochondrial complex I deficiency	Likely pathogenic (1)	criteria provided, single submitter	Aug 27, 2013	RCV000191115.1
Inborn genetic diseases	Pathogenic (1)	criteria provided, single submitter	Jan 30, 2013	RCV000210568.4
not provided	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Dec 16, 2024	RCV000676602.15
Mitochondrial complex 1 deficiency, nuclear type 21	Pathogenic (3)	criteria provided, multiple submitters, no conflicts	Jun 14, 2021	RCV000786780.7

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Likely pathogenic (Aug 27, 2013)	criteria provided, single submitter (Yang et al. 2013) Method: clinical testing	Mitochondrial complex I deficiency (Autosomal recessive inheritance) Affected status: yes Allele origin: germline	Baylor Genetics Study: Adult_WES Accession: SCV000245519.1 First in ClinVar: Sep 29, 2015 Last updated: Sep 29, 2015	Publications: PubMed (1) PubMed: 26633545 Comment: Likely pathogenicity based on finding it once in our laboratory in trans with a pathogenic variant (c.[166G>A;815-27T>C]) in an 18-year-old male with mitochondrial disease Number of individuals with the variant: 1 Zygosity: Homozygote, Single Heterozygote, Compound Heterozygote Age: 10-19 years Sex: male
Pathogenic (Jan 30, 2013)	criteria provided, single submitter (Ambry Autosomal Dominant and X-Linked criteria (10/2015)) Method: clinical testing	Inborn genetic diseases Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000262856.5 First in ClinVar: Apr 09, 2016 Last updated: Dec 07, 2020	Number of individuals with the variant: 1
Pathogenic (Jun 26, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: research	Mitochondrial complex 1 deficiency, nuclear type 21 (Autosomal recessive inheritance) Affected status: yes Allele origin: maternal	Zeviani Lab, University of Cambridge Accession: SCV000924645.1 First in ClinVar: Jul 03, 2019 Last updated: Jul 03, 2019	Comment: Complex I deficiency. Found as compound heterozygous with c.726C>G (p.Phe242Leu). Clinical Features: Leukoencephalopathy (present) , Abnormality of the liver (present) , Renal tubular acidosis (present) , Short stature (present) , Osteoporosis (present) , Neurodevelopmental delay (present) Zygosity: Compound Heterozygote Age: 10-19 years Sex: female Ethnicity/Population group: Caucasian Geographic origin: Italy
Pathogenic (Jun 14, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Mitochondrial complex 1 deficiency, nuclear type 21 Affected status: unknown Allele origin: germline	Revvity Omics, Revvity Accession: SCV002020565.3 First in ClinVar: Nov 29, 2021 Last updated: Feb 04, 2024
Pathogenic (Dec 16, 2024)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001821127.6 First in ClinVar: Sep 08, 2021 Last updated: Dec 22, 2024	Comment: Published functional studies demonstrate a damaging effect, as expression of this variant in E. coli found that it is associated with reduced protein expression and … (more) Published functional studies demonstrate a damaging effect, as expression of this variant in E. coli found that it is associated with reduced protein expression and reduced complex I activity and oxidoreductase activity (PMID: 29982452); 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: 25356970, 29982452, 30897263, 31787496, 32518176, 26633545) (less)
Pathogenic (Sep 13, 2023)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV000802390.2 First in ClinVar: Aug 05, 2018 Last updated: Dec 28, 2024	Publications: PubMed (11) PubMed: 25356970‚ 29982452‚ 30897263‚ 31787496‚ 31917109‚ 31932725‚ 32518176‚ 34827632‚ 34991945‚ 35620925‚ 36280881 Comment: PP3, PM2_moderate, PM3_strong, PS3
Pathogenic (Jul 05, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV003442283.1 First in ClinVar: Feb 07, 2023 Last updated: Feb 07, 2023	Publications: PubMed (5) PubMed: 25356970‚ 30897263‚ 31787496‚ 32518176‚ 29982452 Comment: This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 104 of the NUBPL protein (p.Leu104Pro). … (more) This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 104 of the NUBPL protein (p.Leu104Pro). This variant is present in population databases (rs201430951, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of mitochondrial complex I deficiency (PMID: 25356970, 30897263, 31787496, 32518176). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209179). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NUBPL function (PMID: 29982452). For these reasons, this variant has been classified as Pathogenic. (less)
Pathogenic (Jul 21, 2021)	no assertion criteria provided Method: literature only	MITOCHONDRIAL COMPLEX I DEFICIENCY, NUCLEAR TYPE 21 Affected status: not provided Allele origin: germline	OMIM Accession: SCV001759968.1 First in ClinVar: Jul 24, 2021 Last updated: Jul 24, 2021	Publications: PubMed (1) PubMed: 32518176 Comment on evidence: For discussion of the c.311T-C transition (c.311T-C, NM_025152.3) in the NUBPL gene, resulting in a leu104-to-pro (L104P) substitution, that was identified in compound heterozygous state … (more) For discussion of the c.311T-C transition (c.311T-C, NM_025152.3) in the NUBPL gene, resulting in a leu104-to-pro (L104P) substitution, that was identified in compound heterozygous state in 2 sibs with mitochondrial complex I deficiency nuclear type 21 (MC1DN21; 618242) by Kimonis et al. (2021), see 613621.0008. In a patient (patient 3) with MC1DN21, Kimonis et al. (2021) identified compound heterozygosity for 2 mutations in the NUBPL gene: L104P and c.815-27T-C/R56G (613621.0001). The mutations were identified by whole-exome sequencing, and the parents were shown to be mutation carriers. (less)

Comment:

Published functional studies demonstrate a damaging effect, as expression of this variant in E. coli found that it is associated with reduced protein expression and reduced complex I activity and oxidoreductase activity (PMID: 29982452); 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: 25356970, 29982452, 30897263, 31787496, 32518176, 26633545)

Comment:

This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 104 of the NUBPL protein (p.Leu104Pro). This variant is present in population databases (rs201430951, gnomAD 0.04%). This missense change has been observed in individuals with clinical features of mitochondrial complex I deficiency (PMID: 25356970, 30897263, 31787496, 32518176). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 209179). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects NUBPL function (PMID: 29982452). For these reasons, this variant has been classified as Pathogenic.

Germline Functional Evidence

Functional Help The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence	Method Help A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter.	Result Help A brief description of the result of this method for this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Decreased function	Method not provided	Result not provided	Zeviani Lab, University of Cambridge Accession: SCV000924645.1

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Early embryonic lethality in complex I associated p.L104P Nubpl mutant mice.	Cheng C	Orphanet journal of rare diseases	2022	PMID: 36280881
The fibroblast growth factor 21 concentration in children with mitochondrial disease does not depend on the disease stage, but rather on the disease genotype.	Wesół-Kucharska D	Pediatric endocrinology, diabetes, and metabolism	2022	PMID: 35620925
FGF21 outperforms GDF15 as a diagnostic biomarker of mitochondrial disease in children.	Riley LG	Molecular genetics and metabolism	2022	PMID: 34991945
An Overview of Mitochondrial Protein Defects in Neuromuscular Diseases.	Marra F	Biomolecules	2021	PMID: 34827632
NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum.	Kimonis V	Journal of medical genetics	2021	PMID: 32518176
An engineered enzyme that targets circulating lactate to alleviate intracellular NADH:NAD(+) imbalance.	Patgiri A	Nature biotechnology	2020	PMID: 31932725
Pathogenic variants in NUBPL result in failure to assemble the matrix arm of complex I and cause a complex leukoencephalopathy with thalamic involvement.	Friederich MW	Molecular genetics and metabolism	2020	PMID: 31917109
Novel compound heterozygous pathogenic variants in nucleotide-binding protein like protein (NUBPL) cause leukoencephalopathy with multi-systemic involvement.	Protasoni M	Molecular genetics and metabolism	2020	PMID: 31787496
Mitochondrial complex I NUBPL mutations cause combined dystonia with bilateral striatal necrosis and cerebellar atrophy.	Balint B	European journal of neurology	2019	PMID: 30897263
Pathogenic mutations in NUBPL affect complex I activity and cold tolerance in the yeast model Yarrowia lipolytica.	Maclean AE	Human molecular genetics	2018	PMID: 29982452
Molecular diagnostic experience of whole-exome sequencing in adult patients.	Posey JE	Genetics in medicine : official journal of the American College of Medical Genetics	2016	PMID: 26633545
Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions.	Farwell KD	Genetics in medicine : official journal of the American College of Medical Genetics	2015	PMID: 25356970
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Text-mined citations for rs201430951 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Jan 13, 2025

ClinVar Genomic variation as it relates to human health

NM_025152.3(NUBPL):c.311T>C (p.Leu104Pro)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs201430951 ...