rs199473678

Positions:

chr17-8230304-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_025099.6(CTC1):c.2923A>G(p.Arg975Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000317 in 1,611,172 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

CTC1
NM_025099.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 2.18

Variant links:

Genes affected

CTC1 (HGNC:26169): (CST telomere replication complex component 1) This gene encodes a component of the CST complex. This complex plays an essential role in protecting telomeres from degradation. This protein also forms a heterodimer with the CST complex subunit STN1 to form the enzyme alpha accessory factor. This enzyme regulates DNA replication. Mutations in this gene are the cause of cerebroretinal microangiopathy with calcifications and cysts. Alternate splicing results in both coding and non-coding variants. [provided by RefSeq, Mar 2012]

CTC1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-8230304-T-C is Pathogenic according to our data. Variant chr17-8230304-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 631531.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}. Variant chr17-8230304-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTC1	NM_025099.6 linkuse as main transcript	c.2923A>G	p.Arg975Gly	missense_variant	17/23	ENST00000651323.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTC1	ENST00000651323.1 linkuse as main transcript	c.2923A>G	p.Arg975Gly	missense_variant	17/23		NM_025099.6	P1	Q2NKJ3-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152146

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:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000687

AC:

AN:

247296

Hom.:

AF XY:

0.0000671

AC XY:

AN XY:

134208

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:

0.000151

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000281

AC:

AN:

1459026

Hom.:

Cov.:

AF XY:

0.0000262

AC XY:

AN XY:

725810

show subpopulations

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:

0.0000342

Gnomad4 OTH exome

AF:

0.0000498

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152146

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74322

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:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000575

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000579

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 13, 2023	Published functional studies demonstrate a damaging effect with global genome instabilities under replication stress (Wang et al., 2018); 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: 23869908, 32033110, 24115768, 22267198, 32499435, 22387016, 34308104, 37495394, 37021555, 29481669) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Dyskeratosis congenita

Pathogenic:1Uncertain:1

Likely pathogenic, criteria provided, single submitter	curation	Sema4, Sema4	Sep 28, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 15, 2022	This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 975 of the CTC1 protein (p.Arg975Gly). This variant is present in population databases (rs199473678, gnomAD 0.02%). This missense change has been observed in individuals with Coats plus syndrome (PMID: 22267198, 22387016, 22899577). ClinVar contains an entry for this variant (Variation ID: 631531). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CTC1 function (PMID: 23869908, 24115768, 29481669). 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. -

Cerebroretinal microangiopathy with calcifications and cysts 1

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2019

The CTC1 c.2923A>G (p.Arg975Gly) missense variant has been reported in two studies in which it is found in a compound heterozygous state with a null variant in two individuals with cerebroretinal microangiopathy with calcifications and cysts (CRMCC or Coats Plus syndrome) (Anderson et al. 2012; Polvi et al. 2012). The p.Arg975Gly variant was absent from 2,097 control subjects but is reported at a frequency of 0.000154 in the European (non-Finnish) population of the Genome Aggregation Database. Functional studies demonstrate that the p.Arg975Gly variant was found to reduce telomere association in vivo to 83% that of wild type, while other telomeric functions were found to be preserved, similar to those of wild type (Chen et al. 2013). Wang et al. (2018) showed that unlike wild type CTC1, the p.Arg975Gly variant failed to completely restore the chromosome abnormalities, RAD51 foci formation, and proliferation defects caused by CTC1 knockdown in cells and that the p.Arg975Gly variant significantly reduced CTC1 association to genomic fragile sites in response to replication stress indicating that this residue might be critical for RAD51 binding. Based on the evidence, the p.Arg975Gly variant is classified as likely pathogenic for CTC1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.053

BayesDel_noAF

Uncertain

0.090

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.70

D;.

Eigen

Benign

-0.046

Eigen_PC

Benign

-0.056

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.050

MetaRNN

Uncertain

0.63

D;D

MetaSVM

Benign

-0.42

MutationAssessor

Uncertain

2.4

M;.

MutationTaster

Benign

5.8e-7

PrimateAI

Benign

0.37

PROVEAN

Pathogenic

-5.3

D;.

REVEL

Uncertain

0.56

Sift

Uncertain

0.0040

D;.

Sift4G

Uncertain

0.011

D;D

Polyphen

0.73

P;.

Vest4

0.40

MVP

0.66

MPC

0.38

ClinPred

0.42

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.64

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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