The c.2108C>T (p.T703M) alteration is located in exon 6 (coding exon 6) of the BICD2 gene. This alteration results from a C to T substitution at nucleotide position 2108, causing the threonine (T) at amino acid position 703 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/281794) total alleles studied. The highest observed frequency was 0.004% (1/24960) of African alleles. This alteration was detected in multiple individuals with features consistent with lower extremity-predominant spinal muscular atrophy 2 (Storbeck, 2017; Unger, 2016; Neveling, 2013). This amino acid position is highly conserved in available vertebrate species. Multiple functional assays show aberrant protein function and mis-localization of protein in vitro and in vivo (Unger, 2016; Neveling, 2013; Martinez Carrera, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
ClinVar Genomic variation as it relates to human health
NM_001003800.2(BICD2):c.2108C>T (p.Thr703Met)
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.
(7)
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/Likely pathogenic
7
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.2108C>T (p.Thr703Met)
Variation ID: 55858 Accession: VCV000055858.12
- Type and length
-
single nucleotide variant, 1 bp
- Location
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Cytogenetic: 9q22.31 9: 92717947 (GRCh38) [ NCBI UCSC ] 9: 95480229 (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 Dec 6, 2016 May 1, 2024 Dec 8, 2022 - HGVS
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... more HGVS ... less HGVSNucleotide Protein Molecular
consequenceNM_001003800.2:c.2108C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_001003800.1:p.Thr703Met missense NM_015250.4:c.2108C>T NP_056065.1:p.Thr703Met missense NC_000009.12:g.92717947G>A NC_000009.11:g.95480229G>A NG_033908.1:g.51855C>T Q8TD16:p.Thr703Met - Protein change
- T703M
- Other names
- -
- Canonical SPDI
- NC_000009.12:92717946: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.
-
The Genome Aggregation Database (gnomAD), exomes 0.00000
Trans-Omics for Precision Medicine (TOPMed) 0.00000
Exome Aggregation Consortium (ExAC) 0.00001
The Genome Aggregation Database (gnomAD) 0.00001
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00008
- 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 (5) |
criteria provided, multiple submitters, no conflicts
|
Sep 7, 2022 | RCV000049275.16 | |
| Pathogenic (1) |
criteria provided, single submitter
|
Apr 5, 2016 | RCV000345846.1 | |
| Likely pathogenic (1) |
criteria provided, single submitter
|
Dec 8, 2022 | RCV002513674.2 |
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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Likely pathogenic
(Dec 08, 2022)
|
criteria provided, single submitter
Method: clinical testing
|
Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
|
Ambry Genetics
Accession: SCV003656651.2
First in ClinVar: Feb 07, 2023 Last updated: May 01, 2024 |
Comment:
The c.2108C>T (p.T703M) alteration is located in exon 6 (coding exon 6) of the BICD2 gene. This alteration results from a C to T substitution … (more)
The c.2108C>T (p.T703M) alteration is located in exon 6 (coding exon 6) of the BICD2 gene. This alteration results from a C to T substitution at nucleotide position 2108, causing the threonine (T) at amino acid position 703 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/281794) total alleles studied. The highest observed frequency was 0.004% (1/24960) of African alleles. This alteration was detected in multiple individuals with features consistent with lower extremity-predominant spinal muscular atrophy 2 (Storbeck, 2017; Unger, 2016; Neveling, 2013). This amino acid position is highly conserved in available vertebrate species. Multiple functional assays show aberrant protein function and mis-localization of protein in vitro and in vivo (Unger, 2016; Neveling, 2013; Martinez Carrera, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic. (less)
|
|
|
Pathogenic
(Apr 05, 2016)
|
criteria provided, single submitter
Method: clinical testing
|
Not Provided
Affected status: yes
Allele origin:
germline
|
GeneDx
Accession: SCV000329948.5
First in ClinVar: Dec 06, 2016 Last updated: Dec 06, 2016 |
Comment:
The maternally inherited T703M pathogenic variant in the BICD2 gene has been reported previously as aheterozygous pathogenic variant in a father and son with spinal … (more)
The maternally inherited T703M pathogenic variant in the BICD2 gene has been reported previously as aheterozygous pathogenic variant in a father and son with spinal muscular atrophy (Neveling et al., 2013). Usingimmunoblot analysis, fibroblasts from the affected patients had reduced BICD2 levels compared to control fibroblastsand using immunostaining, the fibroblasts from the affected patients showed strong Golgi fragmentation and BICD2trapped in the Golgi (Neveling et al., 2013). The T703M variant was not observed with any significant frequency inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The T703M variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs in the 3rd coiled-coil domain at a position that isconserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. We interpret T703M as a pathogenic variant. (less)
|
|
|
Pathogenic
(-)
|
criteria provided, single submitter
Method: not provided
|
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
(Autosomal dominant inheritance)
Affected status: yes
Allele origin:
germline
|
Institute of Human Genetics, University Hospital of Duesseldorf
Accession: SCV004046801.1
First in ClinVar: Oct 21, 2023 Last updated: Oct 21, 2023 |
|
|
|
Pathogenic
(Sep 07, 2022)
|
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: SCV000773375.7
First in ClinVar: Jan 09, 2018 Last updated: Feb 14, 2024 |
Comment:
Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116, 27784775, 29528393). Algorithms developed to predict the effect of missense changes on … (more)
Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116, 27784775, 29528393). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 55858). This missense change has been observed in individual(s) with clinical features of BICD2-related conditions (PMID: 23664116, 27784775, 28635954; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs371707778, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 703 of the BICD2 protein (p.Thr703Met). For these reasons, this variant has been classified as Pathogenic. (less)
|
|
|
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: SCV000077532.3
First in ClinVar: Aug 01, 2013 Last updated: Feb 04, 2019 |
Comment on evidence:
In a father and son of Canadian descent with autosomal dominant lower extremity-predominant spinal muscular atrophy-2A (SMALED2A; 615290), originally reported by Adams et al. (1998), … (more)
In a father and son of Canadian descent with autosomal dominant lower extremity-predominant spinal muscular atrophy-2A (SMALED2A; 615290), originally reported by Adams et al. (1998), Neveling et al. (2013) identified a heterozygous c.2108C-T transition in a CpG dinucleotide in exon 6 of the BICD2 gene, resulting in a thr703-to-met (T703M) substitution at a highly conserved residue in the fifth coiled-coil domain. The mutation was not found in several large control exome databases. In a German patient with SMALED2A, Unger et al. (2016) identified a heterozygous T703M mutation, which was later found to be inherited from his clinically unaffected mother (Storbeck et al., 2017). The mutation was found at a low frequency in the gnomAD database (7.1 x 10(-6)). (less)
|
|
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Likely pathogenic
(-)
|
no assertion criteria provided
Method: clinical testing
|
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
Affected status: yes
Allele origin:
germline
|
Genomics England Pilot Project, Genomics England
Accession: SCV001760245.1
First in ClinVar: Jul 27, 2021 Last updated: Jul 27, 2021 |
|
|
|
Uncertain significance
(Jan 06, 2016)
|
no assertion criteria provided
Method: literature only
|
Autosomal dominant childhood-onset proximal spinal muscular atrophy with contractures
Affected status: yes
Allele origin:
germline
|
Inherited Neuropathy Consortium Ii, University Of Miami
Accession: SCV004011899.1
First in ClinVar: Jul 16, 2023 Last updated: Jul 16, 2023 |
|
Comment:
Comment:
The maternally inherited T703M pathogenic variant in the BICD2 gene has been reported previously as aheterozygous pathogenic variant in a father and son with spinal muscular atrophy (Neveling et al., 2013). Usingimmunoblot analysis, fibroblasts from the affected patients had reduced BICD2 levels compared to control fibroblastsand using immunostaining, the fibroblasts from the affected patients showed strong Golgi fragmentation and BICD2trapped in the Golgi (Neveling et al., 2013). The T703M variant was not observed with any significant frequency inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The T703M variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs in the 3rd coiled-coil domain at a position that isconserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. We interpret T703M as a pathogenic variant.
Comment:
Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116, 27784775, 29528393). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 55858). This missense change has been observed in individual(s) with clinical features of BICD2-related conditions (PMID: 23664116, 27784775, 28635954; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs371707778, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 703 of the BICD2 protein (p.Thr703Met). For these reasons, this variant has been classified as Pathogenic.
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:
The c.2108C>T (p.T703M) alteration is located in exon 6 (coding exon 6) of the BICD2 gene. This alteration results from a C to T substitution at nucleotide position 2108, causing the threonine (T) at amino acid position 703 to be replaced by a methionine (M). Based on data from gnomAD, the T allele has an overall frequency of 0.001% (2/281794) total alleles studied. The highest observed frequency was 0.004% (1/24960) of African alleles. This alteration was detected in multiple individuals with features consistent with lower extremity-predominant spinal muscular atrophy 2 (Storbeck, 2017; Unger, 2016; Neveling, 2013). This amino acid position is highly conserved in available vertebrate species. Multiple functional assays show aberrant protein function and mis-localization of protein in vitro and in vivo (Unger, 2016; Neveling, 2013; Martinez Carrera, 2018). The in silico prediction for this alteration is inconclusive. Based on the available evidence, this alteration is classified as likely pathogenic.
Comment:
The maternally inherited T703M pathogenic variant in the BICD2 gene has been reported previously as aheterozygous pathogenic variant in a father and son with spinal muscular atrophy (Neveling et al., 2013). Usingimmunoblot analysis, fibroblasts from the affected patients had reduced BICD2 levels compared to control fibroblastsand using immunostaining, the fibroblasts from the affected patients showed strong Golgi fragmentation and BICD2trapped in the Golgi (Neveling et al., 2013). The T703M variant was not observed with any significant frequency inapproximately 6500 individuals of European and African American ancestry in the NHLBI Exome SequencingProject, indicating it is not a common benign variant in these populations. The T703M variant is a non-conservativeamino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity,charge, size and/or other properties. This substitution occurs in the 3rd coiled-coil domain at a position that isconserved across species. In silico analysis predicts this variant is probably damaging to the proteinstructure/function. We interpret T703M as a pathogenic variant.
Comment:
Experimental studies have shown that this missense change affects BICD2 function (PMID: 23664116, 27784775, 29528393). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 55858). This missense change has been observed in individual(s) with clinical features of BICD2-related conditions (PMID: 23664116, 27784775, 28635954; Invitae). In at least one individual the variant was observed to be de novo. This variant is present in population databases (rs371707778, gnomAD 0.004%). This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 703 of the BICD2 protein (p.Thr703Met). For these reasons, this variant has been classified as Pathogenic.
Citations for germline classification of this variant
Help| Title | Author | Journal | Year | Link |
|---|---|---|---|---|
| Novel insights into SMALED2: BICD2 mutations increase microtubule stability and cause defects in axonal and NMJ development. | Martinez Carrera LA | Human molecular genetics | 2018 | PMID: 29528393 |
| Phenotypic extremes of BICD2-opathies: from lethal, congenital muscular atrophy with arthrogryposis to asymptomatic with subclinical features. | Storbeck M | European journal of human genetics : EJHG | 2017 | PMID: 28635954 |
| Expanding the phenotype of BICD2 mutations toward skeletal muscle involvement. | Unger A | Neurology | 2016 | PMID: 27784775 |
| 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 |
| Congenital autosomal dominant distal spinal muscular atrophy. | Adams C | Neuromuscular disorders : NMD | 1998 | PMID: 9713859 |
| Identification of point mutations in 41 unrelated patients affected with Menkes disease. | Tümer Z | American journal of human genetics | 1997 | PMID: 8981948 |
Text-mined citations for rs371707778 ...
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 Sep 29, 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.