9-134835127-C-T
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2PP3_ModerateBP6BS2
The NM_000093.5(COL5A1):c.5293C>T(p.Arg1765Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000459 in 1,613,726 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1765H) has been classified as Likely benign.
Frequency
Consequence
NM_000093.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A1 | NM_000093.5 | c.5293C>T | p.Arg1765Cys | missense_variant | 65/66 | ENST00000371817.8 | |
LOC101448202 | NR_103451.2 | n.71-14918G>A | intron_variant, non_coding_transcript_variant | ||||
COL5A1 | NM_001278074.1 | c.5293C>T | p.Arg1765Cys | missense_variant | 65/66 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A1 | ENST00000371817.8 | c.5293C>T | p.Arg1765Cys | missense_variant | 65/66 | 1 | NM_000093.5 | P4 | |
COL5A1 | ENST00000371820.4 | c.5293C>T | p.Arg1765Cys | missense_variant | 65/66 | 2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000723 AC: 11AN: 152212Hom.: 1 Cov.: 33
GnomAD3 exomes AF: 0.0000996 AC: 25AN: 250950Hom.: 0 AF XY: 0.000118 AC XY: 16AN XY: 135768
GnomAD4 exome AF: 0.0000431 AC: 63AN: 1461514Hom.: 0 Cov.: 33 AF XY: 0.0000605 AC XY: 44AN XY: 727094
GnomAD4 genome AF: 0.0000723 AC: 11AN: 152212Hom.: 1 Cov.: 33 AF XY: 0.0000538 AC XY: 4AN XY: 74360
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Sep 01, 2022 | COL5A1: PP3 - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 21, 2023 | Has not been previously published as pathogenic or benign in association with cEDS to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (Symoens et al., 2012; HGMD); This variant is associated with the following publications: (PMID: 22696272, 32508047) - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2022 | The p.R1765C variant (also known as c.5293C>T), located in coding exon 65 of the COL5A1 gene, results from a C to T substitution at nucleotide position 5293. The arginine at codon 1765 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ehlers-Danlos syndrome type 7A Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 24, 2023 | Variant summary: COL5A1 c.5293C>T (p.Arg1765Cys) results in a non-conservative amino acid change located in the Fibrillar collagen, C-terminal (IPR000885) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 250950 control chromosomes (gnomAD). The observed variant frequency is approximately 3-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05), strongly suggesting that the variant is benign. c.5293C>T has been reported in the literature in an individual affected with Atrioventricular nodal reentry tachycardia as well as an unaffected control (Luo_2020). This report does not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five submitters have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as uncertain significance (n=4) or benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at