Submissions for variant NM_001003800.2(BICD2):c.320C>T (p.Ser107Leu)

dbSNP: rs398123028

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000049274	SCV000773374	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2023-08-30	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (Invitae) did not meet the statistical confidence thresholds required to predict the impact of this variant on BICD2 function. ClinVar contains an entry for this variant (Variation ID: 55857). This missense change has been observed in individual(s) with spinal muscular atrophy (SMA) (PMID: 23664116, 23664119, 23664120, 25497877, 27784775, 28251916). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 107 of the BICD2 protein (p.Ser107Leu).
GeneDx	RCV001546050	SCV001765497	pathogenic	not provided	2023-01-17	criteria provided, single submitter	clinical testing	Published functional studies demonstrate that this variant alters protein function by increasing protein binding affinity and causing the abnormal accumulation of BICD2 protein (Peeters et al., 2013; Oates et al., 2013; Unger et al., 2016); Missense variants in this gene are often considered pathogenic (HGMD); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26063656, 23664119, 25497877, 23664116, 27784775, 26594138, 28251916, 28883039, 23664120, 29528393, 22628388, 8114789, 31127727, 32056343)
Mayo Clinic Laboratories, Mayo Clinic	RCV001546050	SCV002520038	pathogenic	not provided	2021-07-23	criteria provided, single submitter	clinical testing	PP1, PM1, PM2, PM6, PS3, PS4_moderate
Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria	RCV000049274	SCV002758761	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2022-12-07	criteria provided, single submitter	clinical testing	The c.320C>T (p.Ser107Leu) BICD2 variant has been reported in our laboratory in a 29-year-old patient from Uruguay with diagnosis of distal muscular attrophy. This variant is a de novo change (parents and two asymptomatic siblings) and it has been previously reported in a patients with spinal muscular atrophy [PMID 8114789, 22628388, 23664116, 23664119, 23664120, 25497877, 27784775, 28251916]. This variant is not present in population databases ( gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 55857). In silico analysis (CADD, Mutation Taster, SIFT, Provean, PolyPhen2) supports that this missense variant has a deleterious effect on protein structure/function. Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116). In summary, c.523C>T TRPC6 variant meets our criteria to be classified as pathogenic based upon its absence from controls, computational evidence of pathogenicity and experimental studies, de novo occurrence in this family and having been widely described in relation to the patient´s phenotype.
OMIM	RCV000049274	SCV000077531	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2013-06-06	no assertion criteria provided	literature only
GenomeConnect, ClinGen	RCV000509172	SCV000606905	not provided	Spinal muscular atrophy		no assertion provided	phenotyping only	GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Institute of Human Genetics, Cologne University	RCV000049274	SCV000787773	pathogenic	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	2018-04-25	no assertion criteria provided	clinical testing
Inherited Neuropathy Consortium	RCV000789078	SCV000928427	pathogenic	Neuronopathy, distal hereditary motor, autosomal dominant		no assertion criteria provided	literature only