VCV000055857.16 - ClinVar

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

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(9)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

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

Variation ID: 55857 Accession: VCV000055857.16

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 9q22.31 9: 92729157 (GRCh38) [ NCBI UCSC ] 9: 95491439 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Oct 16, 2017	Nov 10, 2024	Aug 30, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_001003800.2:c.320C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_001003800.1:p.Ser107Leu	missense
NM_015250.4:c.320C>T	NP_056065.1:p.Ser107Leu	missense
NC_000009.12:g.92729157G>A
NC_000009.11:g.95491439G>A
NG_033908.1:g.40645C>T
	Q8TD16:p.Ser107Leu

... more HGVS ... less HGVS

Protein change

S107L

Other names

Canonical SPDI

NC_000009.12:92729156:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

Links

ClinGen: CA143964 UniProtKB: Q8TD16#VAR_070112 OMIM: 609797.0001 dbSNP: rs398123028 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
BICD2		-	-	GRCh38 GRCh37	818	860

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures	Pathogenic (4)	criteria provided, multiple submitters, no conflicts	Aug 30, 2023	RCV000049274.14
Spinal muscular atrophy	not provided (1)	no classification provided	-	RCV000509172.1
Neuronopathy, distal hereditary motor, autosomal dominant	Pathogenic (1)	no assertion criteria provided	-	RCV000789078.1
not provided	Pathogenic (2)	criteria provided, multiple submitters, no conflicts	Jan 17, 2023	RCV001546050.7
Distal myopathy	Pathogenic (1)	criteria provided, single submitter	Apr 17, 2019	RCV004776427.1

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (Jul 23, 2021)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Not provided Affected status: unknown Allele origin: germline	Mayo Clinic Laboratories, Mayo Clinic Accession: SCV002520038.1 First in ClinVar: May 28, 2022 Last updated: May 28, 2022	Publications: PubMed (5) PubMed: 23664116‚ 23664119‚ 23664120‚ 25497877‚ 27784775 Comment: PP1, PM1, PM2, PM6, PS3, PS4_moderate
Pathogenic (Aug 30, 2023)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000773374.8 First in ClinVar: Jan 08, 2018 Last updated: Feb 14, 2024	Publications: PubMed (7) PubMed: 28492532‚ 23664116‚ 23664119‚ 23664120‚ 25497877‚ 27784775‚ 28251916 Comment: 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 … (more) 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). (less)
Pathogenic (Apr 17, 2019)	criteria provided, single submitter (ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020) Method: clinical testing	Distal myopathy Affected status: yes Allele origin: germline	Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service Accession: SCV005387852.1 First in ClinVar: Nov 10, 2024 Last updated: Nov 10, 2024	Number of individuals with the variant: 1 Clinical Features: Motor delay (present) , Muscular atrophy (present) , Proximal lower limb amyotrophy (present) , Distal lower limb amyotrophy (present) , Scapular muscle atrophy (present) , … (more) Motor delay (present) , Muscular atrophy (present) , Proximal lower limb amyotrophy (present) , Distal lower limb amyotrophy (present) , Scapular muscle atrophy (present) , Scapular winging (present) , Progressive muscle weakness (present) , Proximal muscle weakness in upper limbs (present) , Proximal muscle weakness in lower limbs (present) , Distal lower limb muscle weakness (present) , Difficulty walking (present) , EMG abnormality (present) , EMG: neuropathic changes (present) , Myofibrillar myopathy (present) , Rimmed vacuoles (present) (less)
Pathogenic (Dec 07, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures (Autosomal dominant inheritance) Affected status: yes Allele origin: de novo	Servicio Canario de Salud, Hospital Universitario Nuestra Sra. de Candelaria Accession: SCV002758761.1 First in ClinVar: Dec 17, 2022 Last updated: Dec 17, 2022	Publications: PubMed (1) PubMed: 8114789 Comment: 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 … (more) 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. (less) Indication for testing: Spinal muscular atrophy Age: 20-29 years Sex: male Ethnicity/Population group: caucasian Geographic origin: Uruguay
Pathogenic (Jan 17, 2023)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001765497.2 First in ClinVar: Aug 07, 2021 Last updated: Feb 07, 2023	Comment: 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 … (more) 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) (less)
Pathogenic (Apr 25, 2018)	no assertion criteria provided Method: clinical testing	Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures Affected status: yes Allele origin: de novo	Institute of Human Genetics, Cologne University Accession: SCV000787773.1 First in ClinVar: Jan 08, 2018 Last updated: Jan 08, 2018
Pathogenic (Jun 06, 2013)	no assertion criteria provided Method: literature only	SPINAL MUSCULAR ATROPHY, LOWER EXTREMITY-PREDOMINANT, 2A, CHILDHOOD ONSET, AUTOSOMAL DOMINANT Affected status: not provided Allele origin: germline	OMIM Accession: SCV000077531.3 First in ClinVar: Jul 25, 2013 Last updated: Feb 04, 2019	Publications: PubMed (6) PubMed: 8114789‚ 23664116‚ 23664119‚ 23664120‚ 22628388‚ 27784775 Comment on evidence: In affected members of a 3-generation Dutch family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2A (SMALED2A; 615290), originally reported by Frijns et al. (1994), … (more) In affected members of a 3-generation Dutch family with autosomal dominant lower extremity-predominant spinal muscular atrophy-2A (SMALED2A; 615290), originally reported by Frijns et al. (1994), Neveling et al. (2013) identified a heterozygous c.320C-T transition at a CpG dinucleotide in the BICD2 gene, resulting in a ser107-to-leu (S107L) substitution at a highly conserved residue in the second of 5 coiled-coil domains. The mutation, which was found by linkage analysis combined with exome sequencing and confirmed by Sanger sequencing, segregated with the disorder and was not found in several large control exome databases. Peeters et al. (2013) identified a heterozygous S107L substitution in affected members of a Bulgarian family of Turkish origin with SMALED2A. The mutation was found by linkage analysis combined with exome sequencing. The S107L substitution occurs in the N-terminal dynein-binding domain. In vitro functional expression studies showed that the mutant protein had enhanced dynein binding and led to accumulation of BICD2 at the microtubule-organizing complex and Golgi fragmentation. In addition, the altered protein had a reduced colocalization with RAB6A (179513), a regulator of vesicle trafficking between the Golgi and the endoplasmic reticulum. Oates et al. (2013) identified a heterozygous S107L mutation in affected members from 3 unrelated families with SMALED2A, including a large Australian family reported by Oates et al. (2012). The mutation in the large Australian family was found by linkage analysis combined with exome sequencing. Haplotype analysis of 2 of the families with the mutation suggested a founder effect. In vitro functional expression studies showed that the S107L mutation caused increased binding to dynein. Oates et al. (2013) suggested that the mutation interfered with neuronal anterograde trafficking, resulting in a block of neurite outgrowth and impaired embryonic development of motor neurons. In affected members of a German family with SMALED2A, Unger et al. (2016) identified a heterozygous S107L mutation in the BICD2 gene. The mutation, which was found by sequencing of a gene panel and confirmed by Sanger sequencing, segregated with the disorder in the family. Unger et al. (2016) noted that the S107L mutation occurs at a CpG dinucleotide, consistent with it being a hotspot mutation. S102L was not found in the ExAC database. (less)
Pathogenic (-)	no assertion criteria provided Method: literature only	Autosomal dominant distal hereditary motor neuropathy Affected status: yes Allele origin: germline	Inherited Neuropathy Consortium Accession: SCV000928427.1 First in ClinVar: Jul 31, 2019 Last updated: Jul 31, 2019	Publications: PubMed (1) PubMed: 23664116
not provided (-)	no classification provided Method: phenotyping only	Spinal muscular atrophy Affected status: yes Allele origin: de novo	GenomeConnect, ClinGen Accession: SCV000606905.1 First in ClinVar: Oct 16, 2017 Last updated: Oct 16, 2017	Comment: 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 … (more) 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. (less) Clinical Features: Premature birth (present) , Abnormal delivery (present) , Abnormality of the amniotic fluid (present) , Short stature (present) , Myopia (present) , Hypopigmentation of the … (more) Premature birth (present) , Abnormal delivery (present) , Abnormality of the amniotic fluid (present) , Short stature (present) , Myopia (present) , Hypopigmentation of the skin (present) , Multiple cafe-au-lait spots (present) , Abnormality of the curvature of the vertebral column (present) , Increased susceptibility to fractures (present) , Abnormality of limb bone morphology (present) , Abnormality of the musculature of the thorax (present) , Abnormality of the musculature of the limbs (present) , Abnormality of muscle morphology (present) , Abnormality of muscle physiology (present) (less) Indication for testing: Diagnostic Age: 10-19 years Sex: female Method: Sanger Sequencing Testing laboratory: GeneDx Date variant was reported to submitter: 2015-01-12 Testing laboratory interpretation: Pathogenic

Comment:

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).

Comment:

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.

Comment:

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)

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Genetic heterogeneity of motor neuropathies.	Bansagi B	Neurology	2017	PMID: 28251916
Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement.	Unger A	Neurology	2016	PMID: 27784775
Phenotypic and molecular insights into spinal muscular atrophy due to mutations in BICD2.	Rossor AM	Brain : a journal of neurology	2015	PMID: 25497877
Mutations in BICD2 cause dominant congenital spinal muscular atrophy and hereditary spastic paraplegia.	Oates EC	American journal of human genetics	2013	PMID: 23664120
Molecular defects in the motor adaptor BICD2 cause proximal spinal muscular atrophy with autosomal-dominant inheritance.	Peeters K	American journal of human genetics	2013	PMID: 23664119
Mutations in BICD2, which encodes a golgin and important motor adaptor, cause congenital autosomal-dominant spinal muscular atrophy.	Neveling K	American journal of human genetics	2013	PMID: 23664116
Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells.	Oates EC	Brain : a journal of neurology	2012	PMID: 22628388
Dominant congenital benign spinal muscular atrophy.	Frijns CJ	Muscle & nerve	1994	PMID: 8114789

Text-mined citations for rs398123028 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Nov 10, 2024

ClinVar Genomic variation as it relates to human health

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

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs398123028 ...