rs145457535

chr17-44902549-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:21 U:1
• Conservation: PhyloP100: 4.28

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]

ACMG classification

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	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	c.461A>C	p.His154Pro	missense_variant	4/4	1	NM_213607.3	P1
CCDC103	ENST00000410006.6	c.461A>C	p.His154Pro	missense_variant	4/4	2		P1
CCDC103	ENST00000357776.6	c.461A>C	p.His154Pro	missense_variant	4/4	2

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152220 Hom.: 0 Cov.: 32

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.: 0 AF XY: 0.00136 AC XY: 185 AN XY: 135870

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.: 1 Cov.: 32 AF XY: 0.00193 AC XY: 1405 AN XY: 727246

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.: 0 Cov.: 32 AF XY: 0.00126 AC XY: 94 AN XY: 74498

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.: 2

Bravo AF: 0.00117

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00153

EpiControl AF: 0.00196

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:21 Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 17 Pathogenic:12

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, no assertion criteria provided	literature only	OMIM	May 13, 2012	- -
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	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. -
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). -
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. -
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	Daryl Scott Lab, Baylor College of Medicine	Apr 11, 2023	- -
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	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Feb 12, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 25, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

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	Invitae	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	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) -
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. -

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2021	- -
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	Eurofins Ntd Llc (ga)	Dec 29, 2015	- -

CCDC103-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 22, 2023

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
Cadd	Benign	23
Dann	Benign	0.86
DEOGEN2	Benign	0.28	T;.;T;.
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.020	T;T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M;.;M;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
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	D
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

Other links and lift over

dbSNP: rs145457535; hg19: chr17-42979917;