rs797045137

Positions:

• chr11-1758994-C-A

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_001909.5(CTSD):​c.446G>T​(p.Gly149Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G149R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CTSD NM_001909.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.34

Genes affected

CTSD (HGNC:2529): (cathepsin D) This gene encodes a member of the A1 family of peptidases. The encoded preproprotein is proteolytically processed to generate multiple protein products. These products include the cathepsin D light and heavy chains, which heterodimerize to form the mature enzyme. This enzyme exhibits pepsin-like activity and plays a role in protein turnover and in the proteolytic activation of hormones and growth factors. Mutations in this gene play a causal role in neuronal ceroid lipofuscinosis-10 and may be involved in the pathogenesis of several other diseases, including breast cancer and possibly Alzheimer's disease. [provided by RefSeq, Nov 2015]

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a chain Cathepsin D light chain (size 97) in uniprot entity CATD_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001909.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.98
• PP5: Variant 11-1758994-C-A is Pathogenic according to our data. Variant chr11-1758994-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 208848.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTSD	NM_001909.5	c.446G>T	p.Gly149Val	missense_variant	4/9	ENST00000236671.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTSD	ENST00000236671.7	c.446G>T	p.Gly149Val	missense_variant	4/9	1	NM_001909.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 10 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 11, 2014

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 22, 2023

Published functional studies demonstrate a damaging effect on enzyme activity (Bunk et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); 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: 34198733, 27926992, 34491000, 27125852, 32326609, 27527004, 25298308, 33681191, 21990111) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	.;.;D;T;.;T;.;T;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.95	D
MutationAssessor	Pathogenic	4.3	.;.;H;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-8.3	.;.;D;.;.;.;.;.;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;.;D;.;.;.;.;.;D;D
Sift4G	Pathogenic	0.0010	.;.;D;.;.;.;.;.;D;.
Polyphen		0.99	.;.;D;.;.;.;.;.;.;.
Vest4		0.99
MutPred		0.83		Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);Gain of sheet (P = 0.0085);.;Gain of sheet (P = 0.0085);.;.;.;
MVP		0.96
MPC		1.6
ClinPred		1.0	D
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.97

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

Other links and lift over

dbSNP: rs797045137; hg19: chr11-1780224;