NM_004859.4:c.3140T>C

Variant names:

• chr17-59681369-T-C
• rs1555607159
• NM_004859.4:c.3140T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B.

Score: 7 - Likely Pathogenic

7

PM1PM2PP3_ModeratePP5

The NM_004859.4(CLTC):​c.3140T>C​(p.Leu1047Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. L1047L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CLTC NM_004859.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.02
• Publications: 0 publications found

Genes affected

CLTC (HGNC:2092): (clathrin heavy chain) Clathrin is a major protein component of the cytoplasmic face of intracellular organelles, called coated vesicles and coated pits. These specialized organelles are involved in the intracellular trafficking of receptors and endocytosis of a variety of macromolecules. The basic subunit of the clathrin coat is composed of three heavy chains and three light chains. [provided by RefSeq, Jul 2008]

PTRH2 (HGNC:24265): (peptidyl-tRNA hydrolase 2) The protein encoded by this gene is a mitochondrial protein with two putative domains, an N-terminal mitochondrial localization sequence, and a UPF0099 domain. In vitro assays suggest that this protein possesses peptidyl-tRNA hydrolase activity, to release the peptidyl moiety from tRNA, thereby preventing the accumulation of dissociated peptidyl-tRNA that could reduce the efficiency of translation. This protein also plays a role regulating cell survival and death. It promotes survival as part of an integrin-signaling pathway for cells attached to the extracellular matrix (ECM), but also promotes apoptosis in cells that have lost their attachment to the ECM, a process called anoikos. After loss of cell attachment to the ECM, this protein is phosphorylated, is released from the mitochondria into the cytosol, and promotes caspase-independent apoptosis through interactions with transcriptional regulators. This gene has been implicated in the development and progression of tumors, and mutations in this gene have been associated with an infantile multisystem neurologic, endocrine, and pancreatic disease (INMEPD) characterized by intellectual disability, postnatal microcephaly, progressive cerebellar atrophy, hearing impairment, polyneuropathy, failure to thrive, and organ fibrosis with exocrine pancreas insufficiency (PMID: 25574476). Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Mar 2015]

PTRH2 Gene-Disease associations (from GenCC):

• neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• infantile multisystem neurologic-endocrine-pancreatic disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 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 0 benign, 3 uncertain in NM_004859.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.931
• PP5: Variant 17-59681369-T-C is Pathogenic according to our data. Variant chr17-59681369-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 488419.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLTC	NM_004859.4	c.3140T>C	p.Leu1047Pro	missense_variant	Exon 20 of 32	ENST00000269122.8	NP_004850.1
CLTC	NM_001288653.2	c.3152T>C	p.Leu1051Pro	missense_variant	Exon 20 of 32		NP_001275582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLTC	ENST00000269122.8	c.3140T>C	p.Leu1047Pro	missense_variant	Exon 20 of 32	1	NM_004859.4	ENSP00000269122.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability, autosomal dominant 56 Pathogenic:1

Oct 20, 2021

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;.;T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-0.42	T
MutationAssessor	Pathogenic	3.9	.;H;H
PhyloP100		8.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-6.7	.;D;D
REVEL	Pathogenic	0.71
Sift	Pathogenic	0.0	.;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0, 1.0	.;D;D
Vest4		0.96
MutPred		0.80		.;Loss of stability (P = 0.0012);Loss of stability (P = 0.0012);
MVP		0.90
MPC		3.2
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.99
Mutation Taster		=2/98	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1555607159; hg19: chr17-57758730;