Table 2 Variant assessment for three glutamic acid to lysine substitutions in COL3A1

From: Atypical COL3A1 variants (glutamic acid to lysine) cause vascular Ehlers–Danlos syndrome with a consistent phenotype of tissue fragility and skin hyperextensibility

 

F1/F4/F5

F2/F6

F3/F7

c.DNA change

c.2044G>A

c.3511G>A

c.721G>A

Protein change

p.Glu682Lys

p.Glu1171Lys

p.Glu241Lys

In silico analysis summarya–e

Pathogenic

Equivocal

Equivocal

Amino acid conservation

Highly conserved

Highly conserved

Moderately conserved

Grantham distance

Small physicochemical difference between Glu and Lys (Grantham dist=56)

Small physicochemical difference between Glu and Lys (Grantham dist=56)

Small physicochemical difference between Glu and Lys (Grantham dist=56)

Frequency

Not seen in gnomAD normal populations—supports pathogenicity

Not seen in gnomAD normal populations—supports pathogenicity

Not seen in gnomAD normal populations—supports pathogenicity

Segregation analysis

F1: Father, son, aunt, and cousins affected and carry the variant; Canadian report also mentions an unaffected family member not carrying the variant; segregates with disease in five generations

F2: Two unaffected family members do not carry the variant

F6: both parents thought to be clinically unaffected but only mother confirmed to not carry variant

F3: Not observed in unaffected parents or unaffected son, uninformative segregation analysis

F7: No segregation analysis available

Supporting literature/database records

 

Supported by the Frank et al. (2015) paper, however this only uses lack of frequency data, AGVD, SIFT, and MutationTaster to support pathogenicity—not ACMG guidelines

In EDS database;f probably pathogenic

Variant classification

PS4, PM2, PP3, PP1-S, PP4—pathogenic

PP5, PS4, PM2—likely pathogenic

PM2, PS4-S, PP5, PM6—likely pathogenic

  1. ACMG American College of Medical Genetics and Genomics, EDS Ehlers–Danlos syndrome.
  2. ahttp://genetics.bwh.harvard.edu/pph2/.
  3. bhttp://sift.jcvi.org/www/SIFT_chr_coords_submit.html.
  4. chttp://mutpred.mutdb.org/.
  5. dhttp://snps.biofold.org/snps-and-go/snps-and-go.html.
  6. eAlamut 2.9.2 e rev.6.
  7. fhttps://eds.gene.le.ac.uk/home.php?select_db=COL3A1.
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