rs879255247

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PP3_ModeratePP5

The NM_004793.4(LONP1):c.2026C>T(p.Pro676Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000692 in 1,445,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

LONP1
NM_004793.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:1

Conservation

PhyloP100: 8.94

Publications

5 publications found

Variant links:

Genes affected

LONP1 (HGNC:9479): (lon peptidase 1, mitochondrial) This gene encodes a mitochondrial matrix protein that belongs to the Lon family of ATP-dependent proteases. This protein mediates the selective degradation of misfolded, unassembled or oxidatively damaged polypeptides in the mitochondrial matrix. It may also have a chaperone function in the assembly of inner membrane protein complexes, and participate in the regulation of mitochondrial gene expression and maintenance of the integrity of the mitochondrial genome. Decreased expression of this gene has been noted in a patient with hereditary spastic paraplegia (PMID:18378094). Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Feb 2013]

LONP1 Gene-Disease associations (from GenCC):

CODAS syndrome
Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
pyruvate dehydrogenase E1-alpha deficiency
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
congenital diaphragmatic hernia
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics, G2P
mitochondrial encephalomyopathy
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
Leigh syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

LONP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_004793.4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

PP5

Variant 19-5694889-G-A is Pathogenic according to our data. Variant chr19-5694889-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 180658.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
LONP1	NM_004793.4 link	c.2026C>T	p.Pro676Ser	missense_variant	Exon 14 of 18	ENST00000360614.8	NP_004784.2
LONP1	NM_001276479.2 link	c.1834C>T	p.Pro612Ser	missense_variant	Exon 15 of 19		NP_001263408.1
LONP1	NM_001276480.1 link	c.1438C>T	p.Pro480Ser	missense_variant	Exon 14 of 18		NP_001263409.1
LONP1	NR_076392.2 link	n.1831C>T		non_coding_transcript_exon_variant	Exon 15 of 19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LONP1	ENST00000360614.8 link	c.2026C>T	p.Pro676Ser	missense_variant	Exon 14 of 18	1	NM_004793.4	ENSP00000353826.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248810

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000692

AC:

AN:

1445332

Hom.:

Cov.:

AF XY:

0.00000419

AC XY:

AN XY:

715262

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33208

American (AMR)

AF:

0.00

AC:

AN:

44454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26008

East Asian (EAS)

AF:

0.00

AC:

AN:

39174

South Asian (SAS)

AF:

0.00

AC:

AN:

85892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5294

European-Non Finnish (NFE)

AF:

0.00000909

AC:

AN:

1099540

Other (OTH)

AF:

0.00

AC:

AN:

59472

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

LONP1-related disorder

Pathogenic:1

Apr 29, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The LONP1 c.2026C>T variant is predicted to result in the amino acid substitution p.Pro676Ser. This variant has been reported in the homozygous state in an individual with CODAS syndrome (Strauss et al. 2015. PubMed ID: 25574826). A functional study in this same publication found that the p.Pro676Ser substitution causes decreased peptidase activity of the encoded protein (Strauss et al. 2015. PubMed ID: 25574826). This variant is reported in 0.00089% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

CODAS syndrome

Pathogenic:1

Jan 08, 2015

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neurodevelopmental disorder

Pathogenic:1

Jun 01, 2022

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Mar 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 676 of the LONP1 protein (p.Pro676Ser). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with CODAS syndrome (PMID: 25574826). ClinVar contains an entry for this variant (Variation ID: 180658). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt LONP1 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects LONP1 function (PMID: 25574826). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Uncertain

0.027

BayesDel_noAF

Benign

-0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

D;T;.;.;T

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.94

D;D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.89

D;D;D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.1

M;.;.;.;.

PhyloP100

8.9

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-7.3

D;.;.;D;.

REVEL

Pathogenic

0.75

Sift

Uncertain

0.0010

D;.;.;D;.

Sift4G

Pathogenic

0.0010

D;D;D;D;D

Polyphen

0.97

D;.;.;.;.

Vest4

0.79

MutPred

0.57

Gain of phosphorylation at P676 (P = 0.1565);.;.;.;.;

MVP

0.52

MPC

0.95

ClinPred

1.0

GERP RS

3.7

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.77

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over