ClinVar Miner

Submissions for variant NM_000090.4(COL3A1):c.1304G>A (p.Gly435Asp)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV002380919 SCV002689933 pathogenic Familial thoracic aortic aneurysm and aortic dissection 2021-02-24 criteria provided, single submitter clinical testing The p.G435D pathogenic mutation (also known as c.1304G>A), located in coding exon 19 of the COL3A1 gene, results from a G to A substitution at nucleotide position 1304. The glycine at codon 435 is replaced by aspartic acid, an amino acid with similar properties. The majority (approximately two-thirds) of COL3A1 mutations identified to date have involved the substitution of another amino acid for glycine within the triple-helical domain (Pepin MG et al. Genet Med. 2014;16(12):881-8; Frank M et al. Eur J Hum Genet. 2015;23(12):1657-64). This particular glycine substitution has been reported in individuals with vascular Ehlers-Danlos (vEDS), including one reportedly de novo case (Frank M et al. Eur J Hum Genet, 2015 Dec;23:1657-64; Callaghan MB et al. Am J Med Genet A, 2020 03;182:553-556). Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif in the COL3A1 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci. U.S.A. 2008;105:18273-7; Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute RCV004785654 SCV005399258 pathogenic Ehlers-Danlos syndrome, type 4 2020-06-11 criteria provided, single submitter clinical testing Based on the classification scheme VCGS_Germline_v1.1.1, this variant is classified as 5-Pathogenic. Following criteria are met: 0104 - Dominant Negative is a mechanism of disease for this gene. (N) 0108 - This gene is known to be associated with both recessive and dominant disease. This gene is associated with autosomal recessive polymicrogyria with or without vascular-type Ehlers-Danlos syndrome and autosomal dominant Ehlers-Danlos syndrome, vascular type (OMIM). (N) 0200 - Variant is predicted to result in a missense amino acid change from glycine to aspartic acid. This variant is in exon 19 of the COL3A1 gene. (N) 0251 - Variant is heterozygous. (N) 0301 - Variant is absent from gnomAD. (P) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (P) 0600 - Variant is located in an annotated domain or motif (Triple helix repeat region; NCBI conserved domain). (N) 0702 - Comparable variants have strong previous evidence for pathogenicity. Multiple variants affecting the glycine residue of a Gly-X-Y repeat in the triple helix repeat domain have been classified as likely pathogenic or pathogenic (ClinVar). However, alternate amino acid changes at the same residue (p.Gly435Cys and p.Gly435Ser) have also been classified as variants of uncertain significance although in silico tools predict both alternate changes to be deleterious (ClinVar). (P) 0803 - Low previous evidence of pathogenicity in unrelated individuals. Variant has been reported in two families diagnosed with vascular Ehlers-Danlos syndrome (PMIDs: 25758994; 31833208). (P) 1007 - No published functional evidence has been identified for this variant in the literature. (N) 1208 - Inheritance information for this variant is not currently available. (N) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign

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