ClinGen / GenCC / BabySeq / HGMD / OMIM | ClinGen has a curation for AD distal hereditary motor neuronopathy (https://search.clinicalgenome.org/kb/genes/HGNC:2961), as well as dosage sensitivity curations. ClinGen dosage sensitivity curations indicate no evidence for triplosensitivity or haploinsufficiency. From ClinGen’s dosage sensitivity curation: “Variants in the N-terminal stem domain are more commonly described in patients with autosomal dominant neuromuscular disease (e.g. autosomal dominant axoxinal Charcot-Marie-Tooth disease type 2O, lower extremity-predominant spinal muscular atrophy-1), whereas variants in the C-terminal motor domain are more commonly reported in patients with intellectual disability (ID) and malformations in cortical development (MCD)”. Not in BabySeq. GenCC: 3 submissions for autosomal dominant childhood-onset proximal spinal muscular atrophy without contractures (definitive, strong, supportive). 1 submission for autosomal dominant non-syndromic intellectual disability (supportive). 2 submissions for Charcot-Marie-Tooth disease axonal type 2O (strong, supportive). 3 submissions for intellectual disability, autosomal dominant 13 (definitive, strong, strong). 1 submission for distal hereditary motor neuronopathy (definitive by ClinGen).
OMIM: AD Charcot-Marie-Tooth disease, axonal, type 2O AD Cortical dysplasia, complex, with other brain malformations 13 AD Spinal muscular atrophy, lower extremity-predominant 1
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Clinical Validity Scoring Notes and points | Variant/Case Evidence (7 points) DYNC1H1 p.del659-662 - 0.6 points Not in GnomAD v4. PMID: 23603762, Patient P144, 15yo with microcephaly, bedridden, spastic tetraplegia, early onset epilepsy, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4)
DYNC1H1 p.K129I - 0.6 points Not in GnomAD v4. REVEL = 0.390. PMID: 23603762, Patient P582, 10yo with severe ID, late onset epilepsy, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4).
DYNC1H1 p.K3336N - 1.1 points Not in GnomAD v4. REVEL = 0.540. PMID: 23603762, Patient P122, 12yo with microcephaly, bedridden, spastic tetraplegia, early onset epilepsy, foot deformities, MRI findings. De novo. Variant identified on exome. (Supp Table 4). Functional studies and showed that this variant showed a significant reduction in microtubule binding affinity compared to WT control (Fig 3d).
DYNC1H1 p.R3384Q- 1.1 points Not in GnomAD v4. REVEL = 0.395 PMID: 23603762, Patient P217, 10yo with microcephaly, bedridden, spastic tetraplegia, early onset epilepsy, foot deformities, MRI findings. De novo. Variant identified on exome. (Supp Table 4). Functional studies and showed that this variant showed a significant reduction in microtubule binding affinity compared to WT control (Fig 3d).
DYNC1H1 p.R1567Q- 0.6 points Not in GnomAD v4. REVEL = 0.508 PMID: 23603762, Patient P398, 7yo with severe ID, no epilepsy and normocephalic, foot deformities, MRI findings. De novo. Variant identified on exome. (Supp Table 4).
DYNC1H1 p.R3344Q- 1.2 points Not in GnomAD v4. REVEL = 0.439 PMID: 23603762, Patient P535, 5yo with severe ID and autistic features, Lennox Gastaut and normocephaly, MRI findings, De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4). PMID: 23603762, Patient 574C, 3 yo with moderate ID and focal seizures, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4).
DYNC1H1 p.R1962C - 0.6 points Not in GnomAD v4. REVEL = 0.441 PMID: 23603762, Patient 360J, 19yo with severe ID and focal seizures, MRI findings. De novo. Variant identified through targeted screening of DYNC1H1, TUBG1, KIF2A, and KIF5C (Supp Table 4).
DYNC1H1 p.Glu1518Lys - 0.6 points Not in GnomAD v4. REVEL = 0.573 PMID: 22368300 - 51yo female with severe ID (never been able to walk or speak), congenital clubfeet, epileptic seizures, short stature, head circumference in 2nd percentile. dysmorphic features. wide lateral and third ventricles on CT scan. De novo p.Glu1518Lys variant identified on trio exome sequencing. Non-paternity and sample mixup were excluded.
DYNC1H1 p.His3822Pro - 0.6 points Not in GnomAD v4. REVEL = 0.718 PMID: 22368300 - male with hypotonia, developmental delay, moderately severe ID, mild dysmorphic features. His3822Pro variant was found on trio exome sequencing, de novo. Non-paternity and sample mixup were excluded. PMID: 21076407 - same case as above. PMID 21076407 is the original report.
Segregation Evidence: Case/Control Evidence: Experimental Evidence: Source: 23603762 26395554 28196890 29243232 P122 and P398, Table 1, Supplementary Table 4 and Fig. 3 | |