Submissions for variant NM_001376.5(DYNC1H1):c.2327C>T (p.Pro776Leu) (rs1057518083)

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Total submissions: 3

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Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000413532	SCV000491475	pathogenic	not provided	2018-09-04	criteria provided, single submitter	clinical testing	The P776L pathogenic variant in the DYNC1H1 gene has been reported previously as a de novo variant in two unrelated families with features of DYNC1H1-related disorder (Ding et al., 2016; Beecroft et al., 2017). The P776L variant is not observed in large population cohorts (Lek et al., 2016). The P776L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This variant occur within the dimerization domain in the stem domain (Peeters et al., 2015). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. We interpret P776L as a pathogenic variant.
Undiagnosed Diseases Network,NIH	RCV000625972	SCV000746573	pathogenic	Spinal muscular atrophy, lower extremity predominant 1, autosomal dominant	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.
Invitae	RCV000809340	SCV000949489	pathogenic	Charcot-Marie-Tooth disease, axonal, type 2O	2019-11-27	criteria provided, single submitter	clinical testing	This sequence change replaces proline with leucine at codon 776 of the DYNC1H1 protein (p.Pro776Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with lower extremity predominant spinal muscular atrophy (PMID: 26846447, 28554554). ClinVar contains an entry for this variant (Variation ID: 372934). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). For these reasons, this variant has been classified as Pathogenic.

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