rs145457535

Positions:

chr17-44902549-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4

The NM_213607.3(CCDC103):c.461A>C(p.His154Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00182 in 1,614,228 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. H154H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0019 ( 1 hom. )

Consequence

CCDC103
NM_213607.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21U:1

Conservation

PhyloP100: 4.28

Variant links:

Genes affected

CCDC103 (HGNC:32700): (coiled-coil domain containing 103) Enables protein homodimerization activity. Involved in axonemal dynein complex assembly; cilium movement; and determination of left/right symmetry. Predicted to be located in axoneme. Predicted to be part of outer dynein arm. Implicated in primary ciliary dyskinesia 17. [provided by Alliance of Genome Resources, Apr 2022]

CCDC103 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 17-44902549-A-C is Pathogenic according to our data. Variant chr17-44902549-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 31698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-44902549-A-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.019673496). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC103	NM_213607.3 linkuse as main transcript	c.461A>C	p.His154Pro	missense_variant	4/4	ENST00000417826.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC103	ENST00000417826.3 linkuse as main transcript	c.461A>C	p.His154Pro	missense_variant	4/4	1	NM_213607.3	P1	Q8IW40-1
CCDC103	ENST00000410006.6 linkuse as main transcript	c.461A>C	p.His154Pro	missense_variant	4/4	2		P1	Q8IW40-1
CCDC103	ENST00000357776.6 linkuse as main transcript	c.461A>C	p.His154Pro	missense_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.00125

AC:

190

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00215

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00119

AC:

300

AN:

251310

Hom.:

AF XY:

0.00136

AC XY:

185

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00323

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00140

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.00188

AC:

2753

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1405

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000760

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00304

Gnomad4 FIN exome

AF:

0.000112

Gnomad4 NFE exome

AF:

0.00212

Gnomad4 OTH exome

AF:

0.00139

GnomAD4 genome

AF:

0.00125

AC:

190

AN:

152338

Hom.:

Cov.:

AF XY:

0.00126

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000849

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.00215

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00149

Hom.:

Bravo

AF:

0.00117

TwinsUK

AF:

0.00351

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.00126

AC:

153

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00153

EpiControl

AF:

0.00196

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 17

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Nov 12, 2018	The CCDC103 c.461A>C (p.His154Pro) variant has been identified in four studies in a total of ten probands with primary ciliary dyskinesia, including nine in a homozygous state and one in a compound heterozygous state (Panizzi et al. 2012; D'Andrea et al 2013; Casey et al 2015; Boaretto et al. 2016). The p.His154Pro variant was also found in a heterozygous state in 13 unaffected family members. The p.His154Pro variant was absent from 180 controls and is reported at a frequency of 0.00333 in the South Asian population of the Exome Aggregation Consortium. In vivo functional studies in zebrafish demonstrated that the p.His154Pro variant mRNA could not rescue a mutant phenotype, while the wild type CCDC103 mRNA was able to rescue the mutant phenotype, demonstrating a lack of function of the p.His154Pro variant protein (Panizzi et al. 2012). Based on the evidence, the p.His154Pro variant is classified as pathogenic for primary ciliary dyskinesia. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 13, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Apr 05, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM3 strong, PP1 moderated, BP4 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense c.461A>C(p.His154Pro) variant in CCDC103 gene has been reported in homozygous state in individuals affected with ciliary dyskinesia (Casey, J.P., et al.,2015). Functional studies have demonstrated a lack of function of the p.His154Pro variant protein (Panizzi JR, et. al.,2012;Shoemark A, et. al.,2018). The p.His154Pro variant is reported with an allele frequency of 0.1% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain Significance/ Likely Pathogenic/ Pathogenic (multiple submission). The amino acid His at position 154 is changed to a Pro changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.His154Pro in CCDC103 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Ciliary dyskinesia, primary, 17, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2-Supporting => Present in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium with allele frequency compatible with recessive disease and high disease prevalence (1:2265 individuals in South Asia populations) (PMID:28790179). PS3 => Well-established functional studies show a deleterious effect (PMID:28790179) (PMID:22581229). PP1-Moderate => PP1 upgraded in strength to Moderate (PMID:26123568,24357714,22581229). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS3,PP4,PP5. This variant was detected in homozygous state. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Feb 12, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory in a homozygous state in an 8-month-old male with CHD (TAPVR, DORV, malposed great vessels), heterotaxy. Heterozygotes are expected to be asymptomatic carriers. -

Primary ciliary dyskinesia

Pathogenic:5

Likely pathogenic, no assertion criteria provided	literature only	Yale Center for Mendelian Genomics, Yale University	Aug 01, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 01, 2023	The p.H154P variant (also known as c.461A>C), located in coding exon 3 of the CCDC103 gene, results from an A to C substitution at nucleotide position 461. The histidine at codon 154 is replaced by proline, an amino acid with similar properties. This variant has been reported in multiple homozygous individuals of various ethnic backgrounds with primary ciliary dyskinesia (PCD); several affected individuals had laterality defects and ciliary analyses showing dynein arm defects (Panizzi JR et al. Nat. Genet., 2012 May;44:714-9; Zariwala MA et al. Am. J. Hum. Genet., 2013 Aug;93:336-45; D'Andrea G et al. Blood, 2013 Dec;122:4289-91; Casey JP et al. BMC Med. Genet., 2015 Jun;16:45). It has also been confirmed in trans with a second varoamt in an affected individual (Boaretto F et al. J Mol Diagn, 2016 11;18:912-922). In a study of 86 South Asian individuals with a clinical history consistent with PCD, 16 were found to be homozygous for this variant. In this study, this variant was often associated with normal nasal nitric oxide, areas of normal ciliary beat frequency, and normal ultrastructure on electron microscopy; however, respiratory capacity was reduced similarly to a comparator group, comprised of South Asian individuals with PCD who were negative for this alteration (Shoemark A et al. Thorax, 2018 02;73:157-166). Injection of the mutant mRNA in smh zebrafish partially rescued the phenotype, suggesting that this may be a hypomorphic variant (Panizzi JR et al. Nat. Genet., 2012 May;44:714-9). In addition, biochemical analysis has shown that the H154P alteration is highly disruptive of oligomerization ability, although mutant protein retains the ability to dimerize (Shoemark A et al. Thorax, 2018 02;73:157-166). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces histidine, which is basic and polar, with proline, which is neutral and non-polar, at codon 154 of the CCDC103 protein (p.His154Pro). This variant is present in population databases (rs145457535, gnomAD 0.3%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 22581229, 23891469, 24357714, 26123568). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31698). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CCDC103 function (PMID: 22581229). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 12, 2018	The p.His154Pro variant in CCDC103 has been reported in 25 homozygous and 1 comp ound heterozygous individuals with Primary ciliary dyskinesia and segregated in 7 affected family members (Panizzi 2012, D'Andrea 2013, Casey 2015, Boaretto 201 6, Shoemark 2017). All of these individuals were homozygous or compound heterozy gous. This variant has also been reported in ClinVar (Variation ID: 31698). This variant has been identified in 0.32% (97/30782) of South Asian chromosomes by t he Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs145457535). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Co mputational prediction tools and conservation analyses do not provide strong sup port for or against an impact to the protein. Functional studies provide some ev idence that the p.His154Pro variant may reduce protein function (Panizzi 2012). However, these types of assays may not accurately represent biological function. In summary, the p.His154Pro variant in CCDC103 meets criteria to be classified as pathogenic for Primary ciliary dyskinesia in an autosomal recessive manner ba sed upon segregation studies, presence in affecteds, and functional evidence. AC MG/AMP Criteria applied: PS4, PP1_Strong; PS3_Moderate. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute Of Molecular Biology And Genetics, Federal Almazov National Medical Research Centre	Dec 11, 2023	The variant has multiple records in ClinVar with pathogenic interpretation (Variation ID: 31698) -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 29, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2021	Published functional studies in zebra fish suggest a damaging effect with partial rescue of axis curvature or cilia motility phenotypes. In addition, reduced cilia beat amplitude or loss of beat coordination and cilia paralysis was observed in respiratory cells from patients homozygous for this variant (Panizzi et al,. 2012); This variant is associated with the following publications: (PMID: 30238669, 24357714, 22581229, 31469207, 23891469, 27637300, 26123568, 31273583, 28790179, 29363216, 31879361, 31980526, 32447765) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -

CCDC103-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The CCDC103 c.461A>C variant is predicted to result in the amino acid substitution p.His154Pro. This variant was found in the homozygous and compound heterozygous state in multiple individuals with primary ciliary dyskinesia (PCD) and laterality defects (Panizzi et al. 2012. PubMed ID: 22581229; Zariwala et al. 2013. PubMed ID: 24094744; D'Andrea et al. 2013. PubMed ID: 24357714; Casey et al. 2015. PubMed ID: 26123568; Boaretto et al. 2016. PubMed ID: 27637300; Fassad et al. 2020. PubMed ID: 31879361; Burwick et al. 2021. PubMed ID: 32447765). Affected individuals had variable defects of the inner and outer dynein arms as well as defects in ciliary beating ranging from loss of beat coordination to complete ciliary paralysis (Panizzi et al. 2012. PubMed ID: 22581229; Zariwala et al. 2013. PubMed ID: 24094744). Heterozygous carriers were not affected (Panizzi et al. 2012. PubMed ID: 22581229; D'Andrea et al. 2013. PubMed ID: 24357714; Casey et al. 2015. PubMed ID: 26123568). This variant is reported in 0.32% of alleles in individuals of South Asian descent in gnomAD. Based on above information, this variant is classified as pathogenic. -

Infertility disorder

Uncertain:1

Uncertain significance, flagged submission

provider interpretation

MAGI's Lab - Research, MAGI Group

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.36

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Benign

DANN

Benign

0.86

DEOGEN2

Benign

0.28

T;.;T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.14

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.59

.;T;.;T

M_CAP

Benign

0.046

MetaRNN

Benign

0.020

T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.5

M;.;M;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-2.4

N;N;N;.

REVEL

Benign

0.24

Sift

Benign

0.053

T;T;T;.

Sift4G

Benign

0.18

T;T;T;T

Polyphen

0.93

P;.;P;.

Vest4

0.68

MVP

0.66

MPC

0.77

ClinPred

0.79

GERP RS

5.6

Varity_R

0.84

gMVP

0.72

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