Submissions for variant NM_001376.5(DYNC1H1):c.1792C>T (p.Arg598Cys)

dbSNP: rs587780564

Total submissions: 13

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Molecular Neurogenomics lab, VIB Department of Molecular Genetics; University of Antwerp	RCV000149555	SCV000191985	pathogenic	Hereditary motor and sensory neuropathy	2013-11-20	criteria provided, single submitter	research	segregates with the phenotype; absent in 179 ethnically matched controls
GeneDx	RCV000255067	SCV000321571	pathogenic	not provided	2024-02-23	criteria provided, single submitter	clinical testing	Published functional studies demonstrate a damaging effect (results in a protein that shows increased binding to the BICD2 adaptor as compared to wild type) (PMID: 25512093); Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28554554, 25484024, 25512093, 26100331, 27549087, 36720598, 37337091, 35899263, 34535505, 35468861, 25497877, 37470033, 31618753, 31130284, 33060286, 34758253, 25609763)
Eurofins Ntd Llc (ga)	RCV000255067	SCV000708036	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000624400	SCV000741139	pathogenic	Inborn genetic diseases	2015-10-28	criteria provided, single submitter	clinical testing
SIB Swiss Institute of Bioinformatics	RCV000755714	SCV000883188	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2018-10-15	criteria provided, single submitter	curation	This variant is interpreted as Likely Pathogenic, for Charcot-Marie-Tooth disease axonal type 20, autosomal dominant. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease. PS3-Moderate => PS3 downgraded in strength to Moderate (https://www.ncbi.nlm.nih.gov/pubmed/25512093). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product.
Fulgent Genetics, Fulgent Genetics	RCV000762919	SCV000893334	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures; Charcot-Marie-Tooth disease axonal type 2O; Intellectual disability, autosomal dominant 13	2018-10-31	criteria provided, single submitter	clinical testing
HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology	RCV000144249	SCV001190314	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2019-08-02	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000755714	SCV001201024	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2022-07-14	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: 139652). This missense change has been observed in individual(s) with lower extremity-predominant spinal muscular atrophy (SMALED) (PMID: 25484024, 25497877, 25512093, 27549087, 28554554). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 598 of the DYNC1H1 protein (p.Arg598Cys).
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000144249	SCV002767314	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2021-05-06	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: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with spinal muscular atrophy, lower extremity-predominant 1 (MIM#158600), intellectual disability (MIM#614563) and Charcot-Marie-Tooth disease, axonal, type 20 (MIM#614228). While there is no clear genotype-phenotype correlation, there is some association between the severity of the variant on protein function and the phenotype that is manifested (PMID: 25512093, PMID: 28196890). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0115 - Variants in this gene are known to have variable expressivity (PMID: 25512093). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to cysteine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0603 - Missense variant in a region that is highly intolerant to missense variation (high constraint region in DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic. It has been shown to segregate within families, and arise de novo, in individuals with spinal muscular atrophy or spinal muscular atrophy with lower extremity predominant (ClinVar, PMID: 25512093, PMID: 28554554). (SP) 1001 - This variant has strong functional evidence supporting abnormal protein function. Functional analysis of patient lymphoblasts indicated an increased binding in adaptor protein BICD2 (PMID: 25512093). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Center for Genetic Medicine Research, Children's National Medical Center	RCV000144249	SCV000154972	likely pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2014-06-10	no assertion criteria provided	research
Genomics England Pilot Project, Genomics England	RCV000755714	SCV001760325	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2O		no assertion criteria provided	clinical testing
Département de Neurologie, Hospices Civils de Lyon	RCV000144249	SCV003836495	likely pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures	2023-02-24	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium Ii, University Of Miami	RCV000755714	SCV004174346	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	2016-01-06	no assertion criteria provided	literature only