Submissions for variant NM_001377.3(DYNC2H1):c.10648T>C (p.Ser3550Pro)

gnomAD frequency: 0.00035  dbSNP: rs200460601

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000210575	SCV000262922	likely pathogenic	Inborn genetic diseases	2024-10-02	criteria provided, single submitter	clinical testing	The p.S3557P variant (also known as c.10669T>C), located in coding exon 71 of the DYNC2H1 gene, results from a T to C substitution at nucleotide position 10669. The serine at codon 3557 is replaced by proline, an amino acid with similar properties. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is moderately conserved in available vertebrate species. This variant has been identified in conjunction with other DYNC2H1 variants in individuals with features consistent with DYNC2H1-related skeletal ciliopathy; in at least one instance, the variants were identified in trans (Baujat G et al. J Med Genet, 2013 Feb;50:91-8; Farwell KD et al. Genet Med, 2015 Jul;17:578-86; Meng L et al. JAMA Pediatr, 2017 Dec;171:e173438; Ambry internal data; external communication). Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000799119	SCV000938768	pathogenic	Jeune thoracic dystrophy	2024-11-30	criteria provided, single submitter	clinical testing	This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 3557 of the DYNC2H1 protein (p.Ser3557Pro). This variant is present in population databases (rs200460601, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of asphyxiating thoracic dystrophy (PMID: 23339108, 25356970, 28973083; internal data). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 225033). 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) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DYNC2H1 protein function. For these reasons, this variant has been classified as Pathogenic.
Baylor Genetics	RCV001333710	SCV001526376	pathogenic	Asphyxiating thoracic dystrophy 3	2018-07-03	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
GeneDx	RCV001560184	SCV001782541	likely pathogenic	not provided	2024-09-05	criteria provided, single submitter	clinical testing	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: 31308072, 25356970, 28973083, 34426522, 23339108)
Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg	RCV004816358	SCV005071697	likely pathogenic	Retinal dystrophy	2023-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV001333710	SCV005680475	likely pathogenic	Asphyxiating thoracic dystrophy 3	2024-06-22	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004742333	SCV005360711	likely pathogenic	DYNC2H1-related disorder	2024-08-01	no assertion criteria provided	clinical testing	The DYNC2H1 c.10669T>C variant is predicted to result in the amino acid substitution p.Ser3557Pro. This variant is also reported as c.10648T>C (p.Ser3550Pro) with transcript NM_001377.2. This variant has been reported in the compound heterozygous state in two patients with asphyxiating thoracic dysplasia (Baujat et al. 2013. PubMed ID: 23339108; Table S3, Farwell et al. 2015. PubMed ID: 25356970) and was also identified in one patient with short-rib thoracic dysplasia 3 with or without polydactyly (Table S3, Meng et al. 2017. PubMed ID: 28973083). This variant is reported in 0.040% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Interpretations for this variant in ClinVar are conflicting, ranging from uncertain significance to likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/225033/). Taken together, we interpret this variant as likely pathogenic.