Submissions for variant NM_001376.5(DYNC1H1):c.2327C>T (p.Pro776Leu)

dbSNP: rs1057518083

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413532	SCV000491475	pathogenic	not provided	2022-07-28	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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: 31607746, 26846447, 28554554, 32703465, 26100331, 25609763, 25512093, 35899263, 33060286)
Undiagnosed Diseases Network, NIH	RCV000625972	SCV000746573	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2018-03-16	criteria provided, single submitter	clinical testing	The c.2327C>T variant in the DYNC1H1 gene has been reported previously (PMCID:4742772). The patient and his 2 similarly affected identical twin brothers were found to carry the variant. The father was mosaic for this variant with mild symptoms.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000809340	SCV000949489	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2023-08-28	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt DYNC1H1 protein function. ClinVar contains an entry for this variant (Variation ID: 372934). This missense change has been observed in individual(s) with lower extremity predominant spinal muscular atrophy (PMID: 26846447, 28554554). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 776 of the DYNC1H1 protein (p.Pro776Leu).
Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	RCV000413532	SCV001447473	pathogenic	not provided	2020-10-23	criteria provided, single submitter	clinical testing
Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	RCV000625972	SCV002061416	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2021-06-24	criteria provided, single submitter	clinical testing	PS2, PP2, PP3, PM1, PM2, PS4_Moderate
Revvity Omics, Revvity	RCV000413532	SCV003823356	pathogenic	not provided	2022-11-28	criteria provided, single submitter	clinical testing
3billion	RCV000625972	SCV003841803	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2023-02-23	criteria provided, single submitter	clinical testing	The variant is not observed in the gnomAD v2.1.1 dataset. Missense changes are a common disease-causing mechanism. Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000372934). The variant has been previously reported as de novo in a similarly affected individual (PMID: 26846447). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
CeGaT Center for Human Genetics Tuebingen	RCV000413532	SCV005330744	pathogenic	not provided	2024-07-01	criteria provided, single submitter	clinical testing	DYNC1H1: PS2:Very Strong, PM2, PS4:Moderate, PP2
Département de Neurologie, Hospices Civils de Lyon	RCV000625972	SCV003836498	likely pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2023-02-24	no assertion criteria provided	clinical testing