Submissions for variant NM_025137.4(SPG11):c.6100C>T (p.Arg2034Ter) (rs118203963)

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000001168	SCV000253955	pathogenic	Spastic paraplegia 11, autosomal recessive	2015-03-30	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal at codon 2034 (p.Arg2034*). It is expected to result in an absent or disrupted protein product. Truncating variants in SPG11 are known to be pathogenic. This particular truncation has been reported in the literature in patients with autosomal recessive hereditary spastic paraplegia. (PMID: 17322883, 18332254, 18079167, 18663179, 19438933.). For these reasons, this variant has been classified as Pathogenic.
Athena Diagnostics Inc	RCV000518418	SCV000615421	pathogenic	not provided	2017-01-20	criteria provided, single submitter	clinical testing
GeneDx	RCV000518418	SCV000748243	pathogenic	not provided	2018-05-08	criteria provided, single submitter	clinical testing	The R2034X nonsense variant in the SPG11 gene has been reported previously in the homozygous state in several unrelated patients with spastic paraplegia with thin corpus callosum (Stevanin et al., 2007). The R2034X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). This pathogenic variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay.
OMIM	RCV000001168	SCV000021318	pathogenic	Spastic paraplegia 11, autosomal recessive	2015-11-10	no assertion criteria provided	literature only
GeneReviews	RCV000001168	SCV000058181	pathologic	Spastic paraplegia 11, autosomal recessive	2013-01-31	no assertion criteria provided	curation	Converted during submission to Pathogenic.
OMIM	RCV000202373	SCV000257388	pathogenic	Charcot-Marie-Tooth disease, axonal type 2X	2015-11-10	no assertion criteria provided	literature only
Baylor Genetics	RCV000414837	SCV000328861	pathogenic	Spastic paraplegia 11, autosomal recessive; Charcot-Marie-Tooth disease, axonal type 2X	2015-05-27	no assertion criteria provided	clinical testing	Our laboratory reported three molecular diagnoses in CA2 (NM_000067.2, c.232+1G>A), MCCC2 (NM_022132.4, c.1015G>A), and SPG11 (NM_025137.3, c.6100C>T) in one individual with clinical features of global developmental delay, developmental regression, autistic features, intellectual disability, hypotonia, ataxia, dysmorphic features, short stature, microcephaly, hyperextensibility, failure to thrive, structural brain abnormalities, skeletal abnormalities, and limb malformation. The CA2 variant has been previously reported as disease-causing [PMID 1301935]. Heterozygotes would be expected to be asymptomatic carriers.