rs879255247

Positions:

• chr19-5694889-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:1
• Conservation: PhyloP100: 8.94

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 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, 6 uncertain in NM_004793.4
• PM2: Very rare variant in population databases, with high coverage
• 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 id is 180658.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}. Variant chr19-5694889-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LONP1	NM_004793.4	c.2026C>T	p.Pro676Ser	missense_variant	14/18	ENST00000360614.8
LONP1	NM_001276479.2	c.1834C>T	p.Pro612Ser	missense_variant	15/19
LONP1	NM_001276480.1	c.1438C>T	p.Pro480Ser	missense_variant	14/18
LONP1	NR_076392.2	n.1831C>T		non_coding_transcript_exon_variant	15/19

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LONP1	ENST00000360614.8	c.2026C>T	p.Pro676Ser	missense_variant	14/18	1	NM_004793.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248810 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135094

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 SAS 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: 10 AN: 1445332 Hom.: 0 Cov.: 32 AF XY: 0.00000419 AC XY: 3 AN XY: 715262

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000909

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

LONP1-related disorder Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2024

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 08, 2015

- -

Neurodevelopmental disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

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

Jun 01, 2022

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

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	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	29
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	D
LIST_S2	Uncertain	0.94	D;D;D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Benign	-0.51	T
MutationAssessor	Pathogenic	3.1	M;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
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	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.77

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

LitVar

Other links and lift over

dbSNP: rs879255247; hg19: chr19-5694900; COSMIC: COSV61501595; COSMIC: COSV61501595;