ClinVar Genomic variation as it relates to human health
NM_007255.3(B4GALT7):c.808C>T (p.Arg270Cys)
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.
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.
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_007255.3(B4GALT7):c.808C>T (p.Arg270Cys)
Variation ID: 5613 Accession: VCV000005613.30
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 5q35.3 5: 177608994 (GRCh38) [ NCBI UCSC ] 5: 177035995 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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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 Nov 13, 2016 Apr 15, 2024 Sep 8, 2023 - HGVS
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Nucleotide Protein Molecular
consequenceNM_007255.3:c.808C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_009186.1:p.Arg270Cys missense NC_000005.10:g.177608994C>T NC_000005.9:g.177035995C>T NG_015977.1:g.13877C>T - Protein change
- R270C
- Other names
- B4GALT7, ARG270CYS (rs28937869)
- Canonical SPDI
- NC_000005.10:177608993:C:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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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.
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0.00000 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00000
The Genome Aggregation Database (gnomAD), exomes 0.00005
Trans-Omics for Precision Medicine (TOPMed) 0.00006
Exome Aggregation Consortium (ExAC) 0.00007
The Genome Aggregation Database (gnomAD) 0.00009
1000 Genomes Project 30x 0.00031
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 | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
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The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
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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. |
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B4GALT7 | - | - |
GRCh38 GRCh37 |
324 | 414 |
Conditions - Germline
Condition
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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
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The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
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The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Pathogenic (3) |
criteria provided, multiple submitters, no conflicts
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Sep 8, 2023 | RCV000005965.14 | |
Likely pathogenic (1) |
no assertion criteria provided
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Nov 1, 2016 | RCV000258718.3 | |
Pathogenic (2) |
criteria provided, multiple submitters, no conflicts
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Dec 22, 2022 | RCV000413846.19 | |
Pathogenic (1) |
criteria provided, single submitter
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May 23, 2019 | RCV000779599.2 | |
Pathogenic (1) |
criteria provided, single submitter
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May 28, 2022 | RCV002482832.2 |
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
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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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Pathogenic
(May 01, 2017)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV001248516.20
First in ClinVar: May 09, 2020 Last updated: Apr 15, 2024 |
Number of individuals with the variant: 1
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Pathogenic
(May 23, 2019)
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criteria provided, single submitter
Method: research
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Lethal skeletal dysplasia
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
maternal
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Institute for Genomic Medicine, Nationwide Children's Hospital
Accession: SCV000914237.1
First in ClinVar: May 27, 2019 Last updated: May 27, 2019 |
Comment:
This variant has been observed in 13 out of 122,110 gnomAD individuals (13 heterozygotes, MAF=0.00005323), making it extremely rare. It is a known pathogenic variant … (more)
This variant has been observed in 13 out of 122,110 gnomAD individuals (13 heterozygotes, MAF=0.00005323), making it extremely rare. It is a known pathogenic variant previously associated with Larsen syndrome of Reunion Island, and is predicted to be damaging by a majority of in silico tools. In vitro enzyme assays confirmed a reduced level of enzyme activity for this variant. (less)
Sex: male
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Pathogenic
(Aug 01, 2020)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, spondylodysplastic type, 1
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
germline
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001429641.1
First in ClinVar: Oct 01, 2020 Last updated: Oct 01, 2020 |
Comment:
A homozygous missense variation in exon 5 of the B4GALT7 gene that results in the amino acid substitution of Cysteine for Arginine at codon 270 … (more)
A homozygous missense variation in exon 5 of the B4GALT7 gene that results in the amino acid substitution of Cysteine for Arginine at codon 270 was detected. The variant previously been detected in patients affected with Ehlers-Danlos syndrome (Jaenken et al 2017). The variant c.808C>T (p.Arg270Cys) has not been reported in the 1000 genomes database and has a minor allele frequency of 0.005% in the gnomAD database. The in silico prediction of the variant are possibly damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. The observed variation has previously been reported in patients affected with Ehlers-Danlos Syndrome and is one of the most prevalent variants. (less)
Clinical Features:
Failure to thrive (present) , Microcephaly (present) , Abnormal facial shape (present) , Proptosis (present) , Low-set ears (present) , Single transverse palmar crease (present) … (more)
Failure to thrive (present) , Microcephaly (present) , Abnormal facial shape (present) , Proptosis (present) , Low-set ears (present) , Single transverse palmar crease (present) , Pectus carinatum (present) , Generalized hypotonia (present) , Flexion contracture (present) , Respiratory distress (present) (less)
Age: 0-9 years
Sex: male
Ethnicity/Population group: Gujarati/Hindu
Geographic origin: India
Method: DNA was used to perform targeted gene capture using a custom capture kit. Libraries were sequenced to mean >80-100X coverage on Illumina sequencing platform. Sequence obtained were aligned to human references genome using BWA program and analyzed using Picard and GATK-Lite toolkit to identify variants in the targeted genes relevant to clinical indication.
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Pathogenic
(Dec 22, 2022)
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criteria provided, single submitter
Method: clinical testing
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Not Provided
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000490422.3
First in ClinVar: Jan 09, 2017 Last updated: Dec 31, 2022 |
Comment:
Published functional studies showed reduction of galactosyltransferase activity which results in reduction of glycosaminoglycans synthesis (Bui et al., 2010; Rahuel-Clermont et al., 2010; Mihalic Mosher … (more)
Published functional studies showed reduction of galactosyltransferase activity which results in reduction of glycosaminoglycans synthesis (Bui et al., 2010; Rahuel-Clermont et al., 2010; Mihalic Mosher et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 28346368, 28882145, 24970356, 30914273, 20809901, 15211654, 20691685, 23956117, 25533962, 24755949, 26940150, 28306225, 28229453, 31614862, 31862401, 31278392, 18158310, 31589614) (less)
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Pathogenic
(May 28, 2022)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome, spondylodysplastic type, 1
Affected status: unknown
Allele origin:
unknown
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Fulgent Genetics, Fulgent Genetics
Accession: SCV002803990.1
First in ClinVar: Dec 31, 2022 Last updated: Dec 31, 2022 |
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Pathogenic
(Sep 08, 2023)
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criteria provided, single submitter
Method: clinical testing
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Ehlers-Danlos syndrome progeroid type
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV002162238.3
First in ClinVar: Mar 28, 2022 Last updated: Feb 14, 2024 |
Comment:
Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) … (more)
Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on B4GALT7 protein function. This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 270 of the B4GALT7 protein (p.Arg270Cys). This variant is present in population databases (rs28937869, gnomAD 0.01%). This missense change has been observed in individuals with B4GALT7-related conditions (PMID: 15211654, 24755949, 25533962, 31278392). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 5613). Experimental studies have shown that this missense change affects B4GALT7 function (PMID: 20691685, 20809901, 31278392). For these reasons, this variant has been classified as Pathogenic. (less)
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Likely pathogenic
(Nov 01, 2016)
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no assertion criteria provided
Method: literature only
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Larsen-like syndrome, B3GAT3 type
(Autosomal recessive inheritance)
Affected status: yes
Allele origin:
inherited
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Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre
Accession: SCV000328258.1
First in ClinVar: Nov 13, 2016 Last updated: Nov 13, 2016 |
Comment:
Clinical exome sequencing revealed NM_007255.1:c.808C>T:p.R270C (NC_000005.9:g.177035995C>T), the same published variant (PMID: 24755949) that causes autosomal recessive Larsen syndrome, so we believe this is a likely … (more)
Clinical exome sequencing revealed NM_007255.1:c.808C>T:p.R270C (NC_000005.9:g.177035995C>T), the same published variant (PMID: 24755949) that causes autosomal recessive Larsen syndrome, so we believe this is a likely pathogenic variant. (less)
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Germline Functional Evidence
Functional
Help
The functional consequence of the variant, based on experimental evidence and provided by the submitter. consequence |
Method
Help
A brief description of the method used to determine the functional consequence of the variant. A citation for the method is included, when provided by the submitter. |
Result
Help
A brief description of the result of this method for 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 functional evidence for the germline classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Decreased function
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Institute for Genomic Medicine, Nationwide Children's Hospital
Accession: SCV000914237.1
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Unknown function
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Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics
Accession: SCV001429641.1
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variation affecting protein
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Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre
Accession: SCV000328258.1
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Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Expansion of B4GALT7 linkeropathy phenotype to include perinatal lethal skeletal dysplasia. | Mihalic Mosher T | European journal of human genetics : EJHG | 2019 | PMID: 31278392 |
Further defining the phenotypic spectrum of B4GALT7 mutations. | Salter CG | American journal of medical genetics. Part A | 2016 | PMID: 26940150 |
Large-scale discovery of novel genetic causes of developmental disorders. | Deciphering Developmental Disorders Study | Nature | 2015 | PMID: 25533962 |
Redefining the progeroid form of Ehlers-Danlos syndrome: report of the fourth patient with B4GALT7 deficiency and review of the literature. | Guo MH | American journal of medical genetics. Part A | 2013 | PMID: 23956117 |
Biochemical and thermodynamic characterization of mutated β1,4-galactosyltransferase 7 involved in the progeroid form of the Ehlers-Danlos syndrome. | Rahuel-Clermont S | The Biochemical journal | 2010 | PMID: 20809901 |
Molecular characterization of β1,4-galactosyltransferase 7 genetic mutations linked to the progeroid form of Ehlers-Danlos syndrome (EDS). | Bui C | FEBS letters | 2010 | PMID: 20691685 |
Changes in heparan sulfate are associated with delayed wound repair, altered cell migration, adhesion and contractility in the galactosyltransferase I (beta4GalT-7) deficient form of Ehlers-Danlos syndrome. | Götte M | Human molecular genetics | 2008 | PMID: 18158310 |
A novel missense mutation in the galactosyltransferase-I (B4GALT7) gene in a family exhibiting facioskeletal anomalies and Ehlers-Danlos syndrome resembling the progeroid type. | Faiyaz-Ul-Haque M | American journal of medical genetics. Part A | 2004 | PMID: 15211654 |
Linkage studies of four fibrillar collagen genes in three pedigrees with Larsen-like syndrome. | Bonaventure J | Journal of medical genetics | 1992 | PMID: 1640425 |
[Dwarfism and hyperlaxity, facial dysmorphism and multiple dislocations. Larsen's syndrome?]. | Payet G | Archives francaises de pediatrie | 1975 | PMID: 1221956 |
Text-mined citations for rs28937869 ...
HelpRecord last updated May 01, 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.