Submissions for variant NM_001376.5(DYNC1H1):c.751C>T (p.Arg251Cys) (rs879253979)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Centre for Mendelian Genomics,University Medical Centre Ljubljana	RCV000414974	SCV000492853	likely pathogenic	Myopathy; Pes cavus; Hammertoe; Distal lower limb amyotrophy	2015-05-11	criteria provided, single submitter	clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen	RCV000512659	SCV000608712	uncertain significance	not provided	2016-05-01	criteria provided, single submitter	clinical testing
Invitae	RCV000649558	SCV000771387	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2O	2019-09-06	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 251 of the DYNC1H1 protein (p.Arg251Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in several individuals affected with spinal muscular atrophy with lower extremity predominant (SMALED) (PMID: 30122514). This variant has also been reported in an individual affected with an abnormality of the nervous system (PMID: 26633542). ClinVar contains an entry for this variant (Variation ID: 374099). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). A different missense substitution at this codon (p.Arg251His) has been determined to be likely pathogenic (PMID: 26392352, Invitae). This suggests that the arginine residue is critical for DYNC1H1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.

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