11-88296207-C-T

Position:

chr11-88296207-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_001814.6(CTSC):c.815G>A(p.Arg272His) variant causes a missense change. The variant allele was found at a frequency of 0.0000105 in 1,613,938 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R272P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CTSC
NM_001814.6 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.06

Variant links:

Genes affected

CTSC (HGNC:2528): (cathepsin C) This gene encodes a member of the peptidase C1 family and lysosomal cysteine proteinase that appears to be a central coordinator for activation of many serine proteinases in cells of the immune system. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate heavy and light chains that form a disulfide-linked dimer. A portion of the propeptide acts as an intramolecular chaperone for the folding and stabilization of the mature enzyme. This enzyme requires chloride ions for activity and can degrade glucagon. Defects in the encoded protein have been shown to be a cause of Papillon-Lefevre syndrome, an autosomal recessive disorder characterized by palmoplantar keratosis and periodontitis. [provided by RefSeq, Nov 2015]

CTSC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1

In a disulfide_bond (size 43) in uniprot entity CATC_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001814.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr11-88296207-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 548504.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.879

PP5

Variant 11-88296207-C-T is Pathogenic according to our data. Variant chr11-88296207-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139656.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=1, Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSC	NM_001814.6 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	6/7	ENST00000227266.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSC	ENST00000227266.10 linkuse as main transcript	c.815G>A	p.Arg272His	missense_variant	6/7	1	NM_001814.6	P1	P53634-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251430

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135880

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461704

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000135

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Papillon-Lefèvre syndrome

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 13, 2018	The p.Arg272His variant in CTSC has been reported in the compound heterozygous s tate with another missense variant in 1 individual with isolated prepubertal per iodontitis (PPP), which is a feature of Papillon-Lefevre syndrome (PLS; Hewitt 2004). This individual had significantly reduced enzyme activity as compared to both a carrier parent and a control individual (Hewitt 2004). The p.Arg272His ha s been identified in 2/129168 of European chromosomes by gnomAD (http://gnomad.b roadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. The majority of pathogenic missense variants in CTSC occur within exons 5-7 where the p.Arg2 72His variant is located. In addition, another variant involving this codon, p.A rg272Pro, is one of the most frequently reported pathogenic missense variants in individuals with Papillon-Lefevre syndrome (Nagy 2014). In summary, although ad ditional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for Papillon-Lefevre syndrome in an autosomal recessive manner. ACMG/AMP criteria applied: PM2, PM 5, PS3_Supporting, PM3_Supporting. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 24, 2018	The CTSC c.815G>A (p.Arg272His) missense variant has been reported in a single study in which it is found in a compound heterozygous state with two other missense variants in one child with prepubertal periodontitis (PPP) characterized by overlapping features of Papillon-Lefevre syndrome (PLS) including severe progressive periodontitis affecting both deciduous and permanent dentition (Hewitt et al. 2004). Control data are unavailable for this variant which is reported at a frequency of 0.000016 in the European (non-Finnish) population of the Genome Aggregation Database but this is based on two alleles in a region of good sequence coverage, so the variant is presumed to be rare. Untransformed lymphocytes from the proband showed CTSC activity that was 1.3% of the control value. It should be noted that while evidence for the p.Arg272His variant is limited, a variant that produces a different amino acid change at the same residue (p.Arg272Pro), has been frequently reported in patients with PLS (Nagy et al. 2014). The p.Arg272His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for Papillon-Lefevre syndrome. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Periodontitis, aggressive 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2004

- -

Papillon-Lefèvre syndrome;C1855627:Haim-Munk syndrome;C4551681:Periodontitis, aggressive 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 10, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg272 amino acid residue in CTSC. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 14974080, 15585850, 19816003). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 expected to disrupt CTSC protein function. ClinVar contains an entry for this variant (Variation ID: 139656). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 272 of the CTSC protein (p.Arg272His). This variant is present in population databases (rs587777534, gnomAD 0.002%). This missense change has been observed in individual(s) with prepubertal periodontitis (PMID: 14974080, 34515563). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Pathogenic

0.37

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

M_CAP

Benign

0.054

MetaRNN

Pathogenic

0.88

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-4.2

REVEL

Pathogenic

0.75

Sift

Benign

0.049

Sift4G

Uncertain

0.052

Polyphen

1.0

Vest4

0.80

MVP

0.96

MPC

0.27

ClinPred

0.99

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.64

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over