Submissions for variant NM_001376.5(DYNC1H1):c.6994C>T (p.Arg2332Cys)

dbSNP: rs1057518961

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414777	SCV000493024	likely pathogenic	Global developmental delay; Seizure; Delayed speech and language development; Microcephaly; Delayed gross motor development	2014-06-06	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001198404	SCV001369331	likely pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2016-01-01	criteria provided, single submitter	clinical testing	This variant was classified as: Likely pathogenic.
Ambry Genetics	RCV001267559	SCV001445740	pathogenic	Inborn genetic diseases	2019-08-19	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001198404	SCV003442718	pathogenic	Charcot-Marie-Tooth disease axonal type 2O	2024-11-07	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 2332 of the DYNC1H1 protein (p.Arg2332Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal dominant intellectual disability (PMID: 25590979, 27754416, 29286531). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 374190). 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 expected to disrupt DYNC1H1 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic.
Duke University Health System Sequencing Clinic, Duke University Health System	RCV003223402	SCV003919013	pathogenic	Intellectual disability, autosomal dominant 13	2023-04-20	criteria provided, single submitter	research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003223402	SCV005883666	pathogenic	Intellectual disability, autosomal dominant 13	2024-12-12	criteria provided, single submitter	clinical testing	Variant summary: DYNC1H1 c.6994C>T (p.Arg2332Cys) results in a non-conservative amino acid change located in the P-loop containing nucleoside triphosphate hydrolases (IPR027417) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This variant was absent in gnomAD V4. c.6994C>T has been reported in the literature as a de novo occurrence in multiple individuals affected with Intellectual disability, autosomal dominant 13 (examples: Zhu_2015, Liu_2022, Internal data). These data indicate that the variant is likely to be associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 36175372, 25590979). ClinVar contains an entry for this variant (Variation ID: 374190). Based on the evidence outlined above, the variant was classified as pathogenic.
Inherited Neuropathy Consortium Ii, University Of Miami	RCV001198404	SCV004174362	uncertain significance	Charcot-Marie-Tooth disease axonal type 2O	2016-01-06	no assertion criteria provided	literature only