ClinVar Miner

Submissions for variant NM_001278074.1(COL5A1):c.4240G>A (p.Gly1414Ser) (rs776709663)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000755968 SCV000249831 uncertain significance not provided 2018-03-02 criteria provided, single submitter clinical testing p.Gly1414Ser (GGC>AGC): c.4240 G>A in exon 55 of the COL5A1 gene (NM_000093.3) The G1414S variant in the COL5A1 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. The G1414S variant is a non-conservative amino acid substitution as these residues differ in polarity, charge, size and/or other properties and is more likely to impact secondary structure. The G1414 residue is well conserved among most species. In silico analysis predicts G1414S is probably damaging to the protein structure/function. The G1414S variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Nevertheless, no mutations affecting nearby residues have been reported in association with EDS, indicating this region of the protein may be tolerant of change. With the clinical and molecular information available at this time, we cannot definitively determine if G1414S is a disease-causing mutation or a rare benign variant.This variant was found in TAAD
Ambry Genetics RCV000617751 SCV000738607 uncertain significance Cardiovascular phenotype 2016-05-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Center for Human Genetics, Inc,Center for Human Genetics, Inc RCV000659460 SCV000781275 uncertain significance Ehlers-Danlos syndrome, classic type 2016-11-01 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000755968 SCV000883657 uncertain significance not provided 2018-03-04 criteria provided, single submitter clinical testing The COL5A1 c.4240G>A; p.Gly1414Ser variant (rs776709663; ClinVar variant ID 212974), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.006% (identified on 15 out of 233,700 chromosomes) and an Ashkenazi Jewish population frequency of 0.12% (identified on 12 out of 9,500 chromosomes). The glycine at position 1414 is highly conserved, considering 12 species, and is located in a conserved Gly-X-Y repeat. Changes to glycine residues in Gly-X-Y motifs in triple helix domains disrupt helix formation and are predicted to be deleterious (Weerakkody 2016); however, the allele frequency in the Ashkenazi Jewish population indicates this may be a tolerated polymorphic change. Based on the available information, the clinical significance of the p.Gly1414Ser variant cannot be determined with certainty.

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