PP1, PM1, PM2, PM6, PS3, PS4_moderate
ClinVar Genomic variation as it relates to human health
NM_001003800.2(BICD2):c.320C>T (p.Ser107Leu)
Germline
Classification
Help
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)
Help
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
9
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
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single nucleotide variant, 1 bp
- Location
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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
-
... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_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 - Protein change
- S107L
- Other names
- -
- Canonical SPDI
- NC_000009.12:92729156:G:A
-
Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
- -
-
Global minor allele
frequency (GMAF) HelpThe 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
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 | ||
|---|---|---|---|---|---|---|
| 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 |
816 | 858 | |
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. |
|---|---|---|---|---|
| Pathogenic (4) |
criteria provided, multiple submitters, no conflicts
|
Aug 30, 2023 | RCV000049274.14 | |
| not provided (1) |
no classification provided
|
- | RCV000509172.1 | |
| Pathogenic (1) |
no assertion criteria provided
|
- | RCV000789078.1 | |
| Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
|
Jan 17, 2023 | RCV001546050.7 | |
| 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. |
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|---|---|---|---|---|---|
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Pathogenic
(Jul 23, 2021)
|
criteria provided, single submitter
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 |
Comment:
PP1, PM1, PM2, PM6, PS3, PS4_moderate
|
|
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Pathogenic
(Aug 30, 2023)
|
criteria provided, single submitter
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 |
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)
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Pathogenic
(Apr 17, 2019)
|
criteria provided, single submitter
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)
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Pathogenic
(Dec 07, 2022)
|
criteria provided, single submitter
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 |
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
|
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Pathogenic
(Jan 17, 2023)
|
criteria provided, single submitter
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)
|
|
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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 |
|
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Pathogenic
(Jun 06, 2013)
|
no assertion criteria provided
Method: literature only
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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 |
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)
|
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Pathogenic
(-)
|
no assertion criteria provided
Method: literature only
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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 |
|
|
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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:
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)
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 significance of the variant.
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:
PP1, PM1, PM2, PM6, PS3, PS4_moderate
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)
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 significance of the variant.
Citations for germline classification of this variant
Help| 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 ...
HelpThese 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
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.