ClinVar Miner

Submissions for variant NM_007255.3(B4GALT7):c.808C>T (p.Arg270Cys) (rs28937869)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000413846 SCV000490422 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing The R270C variant in the B4GALT7 gene has been reported previously as a founder mutation, present in the homozygous state in multiple individuals with Larsen of Reunion Island syndrome (Cartault et al., 2015). In addition, R270C has also been reported as a homozygous or compound heterozygous variant in multiple individuals with features of spondylodysplastic Ehlers-Danlos syndrome (Faiyaz-Ul-Haque et al., 2004; Guo et al., 2013; Fitzgerald et al., 2015; Salter et al., 2016). Functional characterization of the R270C substitution demonstrated reduction of galactosyltransferase activity, which results in reduced glycosaminoglycan synthesis (Bui et al., 2010; Rahuel-Clermont et al., 2010). The R270C variant is observed in 12/111,620 alleles (0.011%) from individuals of non-Finnish European background, and 13/244,220 global alleles (0.0053%) with no homozygous control individuals reported, in large population cohorts (Lek et al., 2016). The R270C variant is a non-conservative amino acid substitution, which occurs at a position in the acceptor binding site, that is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties (Bui et al., 2010). In-silico analyses, including protein predictors and evolutionary conservation, also support a deleterious effect. We interpret R270C as a pathogenic variant.
Institute for Genomic Medicine, Nationwide Children's Hospital RCV000779599 SCV000914237 pathogenic Lethal skeletal dysplasia 2019-05-23 criteria provided, single submitter research 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.
OMIM RCV000005965 SCV000026147 pathogenic Ehlers-Danlos syndrome progeroid type 2015-01-01 no assertion criteria provided literature only
Developmental Genetics Unit,King Faisal Specialist Hospital & Research Centre RCV000258718 SCV000328258 likely pathogenic Multiple joint dislocations, short stature, craniofacial dysmorphism, and congenital heart defects 2016-11-01 no assertion criteria provided literature only 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.

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