ClinVar Miner

Submissions for variant NM_000089.3(COL1A2):c.2123G>A (p.Arg708Gln) (rs72658163)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000413739 SCV000603113 uncertain significance not specified 2016-08-01 criteria provided, single submitter clinical testing
Center for Human Genetics, Inc RCV000680486 SCV000807864 likely benign Connective tissue disorder 2018-06-01 criteria provided, single submitter clinical testing
GeneDx RCV000413739 SCV000490478 uncertain significance not specified 2016-10-04 criteria provided, single submitter clinical testing The R708Q variant (also known as R618Q) in the COL1A2 gene has been published in association with a variant form of Marfan syndrome (Phillips et al., 1990); the patient had inherited this variant from his mildly affected father. The variant was later reported in a patient with osteogenesis imperfecta (OI) who also harbored a de novo pathogenic variant on the same allele; R708Q was paternally inherited and the father was not noted to have OI (Folino et al., 1998). Additionally, R708Q has been reported in one individual with atypical femoral fractures and suspected hypophosphatasia; however, this individual lacked other clinical features of a COL1A2-related disorder (Taillandier et al., 2015). Although the R708Q variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, this variant was observed in 22/11,554 (0.19%) alleles from individuals of Latino ancestry, 52/66,692 (0.08%) alleles from individuals of European ancestry, and 9/10,402 (0.09%) alleles from individuals of African ancestry in the Exome Aggregation Consortium data set, indicating it may be a rare variant in these populations. The R708Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. As an alternate mechanism, some splice predictor models indicate that this sequence change may create a new cryptic splice acceptor site in exon 35, which may cause abnormal gene splicing; however, in the absence of RNA/functional studies, the actual effect of this sequence change in this individual is unknown. We interpret R708Q as a variant of uncertain significance.
Invitae RCV000533779 SCV000627306 likely benign Ehlers-Danlos syndrome, classic type; Osteogenesis imperfecta type I 2017-07-05 criteria provided, single submitter clinical testing
OMIM RCV000018790 SCV000039073 uncertain significance Marfan syndrome, atypical 2004-06-01 no assertion criteria provided literature only

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