Submissions for variant NM_004928.3(CFAP410):c.218G>C (p.Arg73Pro)

dbSNP: rs140451304

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Blueprint Genetics	RCV001075775	SCV001241408	pathogenic	Retinal dystrophy	2019-06-26	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001091473	SCV001247540	pathogenic	not provided	2024-04-01	criteria provided, single submitter	clinical testing	CFAP410: PM3:Very Strong, PP1:Strong, PM2, PS3:Supporting, BP4
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001091473	SCV001369095	likely pathogenic	not provided	2019-04-28	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PP5.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001091473	SCV001411421	pathogenic	not provided	2025-01-08	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 73 of the CFAP410 protein (p.Arg73Pro). This variant is present in population databases (rs140451304, gnomAD 0.07%). This missense change has been observed in individuals with Jeune asphyxiating thoracic dystrophy, cone-rod dystrophy or retinitis pigmentosa (PMID: 26167768, 27596865). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 428573). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CFAP410 protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects CFAP410 function (PMID: 26167768). For these reasons, this variant has been classified as Pathogenic.
Ocular Genomics Institute, Massachusetts Eye and Ear	RCV001376208	SCV001573267	likely pathogenic	Retinal dystrophy with or without macular staphyloma	2021-04-08	criteria provided, single submitter	research	The C21orf2 c.218G>C variant was identified in an individual with retinitis pigmentosa with a presumed recessive inheritance pattern. Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PP1. Based on this evidence we have classified this variant as Likely Pathogenic.
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	RCV000504803	SCV001950220	likely pathogenic	Retinitis pigmentosa	2021-04-01	criteria provided, single submitter	curation	The p.Arg73Pro variant in C21orf2 was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PM2, PS3, PP1. Based on this evidence we have classified this variant as Likely pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
GeneDx	RCV001091473	SCV002064174	pathogenic	not provided	2022-01-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect with loss of C21orf2 protein function (Wheway et al., 2015); 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: 27596865, 26974433, 26167768, 28422394, 28041643, 29343210, 31980526, 28771251, 32036094, 32581362, 31431468)
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV001075775	SCV005072730	pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001376208	SCV005398911	pathogenic	Retinal dystrophy with or without macular staphyloma	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with retinal dystrophy with macular staphyloma (MIM#617547) and axial spondylometaphyseal dysplasia (MIM#602271). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to proline. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v2: 90 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid changes at the same position has been observed in gnomAD (v2) (highest allele count: 5 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and low conservation. (I) 0600 - Variant is located in the annotated leucine-rich repeat domain (PMID: 26974433). (I) 0710 - Other missense variants comparable to the one identified in this case have inconclusive previous evidence for pathogenicity. The variants p.(Arg73Gly), p.(Arg73Cys), and p.(Arg73His) have each been reported as variants of uncertain significance by a clinical laboratory (ClinVar). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. It has been reported in multiple individuals with axial spondylometaphyseal dysplaisa (PMID: 26974433) and Jeune asphyxiating thoracic dystrophy (PMIDs: 26167768, 28422394). In addition, it has been reported as pathogenic/likely pathogenic by multiple clinical laboratories (ClinVar). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
OMIM	RCV000492059	SCV000580653	pathogenic	Axial spondylometaphyseal dysplasia	2015-08-01	no assertion criteria provided	literature only
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504803	SCV000599093	likely pathogenic	Retinitis pigmentosa	2015-01-01	no assertion criteria provided	research
NIHR Bioresource Rare Diseases, University of Cambridge	RCV000504995	SCV000599094	likely pathogenic	Cone dystrophy	2015-01-01	no assertion criteria provided	research
PreventionGenetics, part of Exact Sciences	RCV003409679	SCV004109827	pathogenic	CFAP410-related disorder	2024-09-10	no assertion criteria provided	clinical testing	The CFAP410 c.218G>C variant is predicted to result in the amino acid substitution p.Arg73Pro. This variant has been reported as segregating with disease in both the homozygous and compound heterozygous states in kindreds with Jeune syndrome or cone-rod dystrophy (Table S8, Wheway et al. 2015. PubMed ID: 26167768). This variant has also been reported along with a second CFAP410 variant in large cohort studies of retinal disease (Table S2, Carss et al. 2017. PubMed ID: 28041643; Zhang et al. 2016. PubMed ID: 27596865; Table S1, Lin. 2024. PubMed ID: 38219857). Additionally, this variant has been reported in the homozygous state in two families with axial spondylometaphyseal dysplasia (Wang et al. 2016. PubMed ID: 26974433). Functional studies suggested that p.Arg73Pro is a hypomorphic variant (Wheway et al. 2015. PubMed ID: 26167768). This variant is reported in 0.065% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic for autosomal recessive CFAP410-related disorders.