rs1554726251

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000093.5(COL5A1):​c.5165dup​(p.Val1723CysfsTer55) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Consequence

COL5A1
NM_000093.5 frameshift

Scores

Not classified

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.15
Variant links:
Genes affected
COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-134834996-A-AC is Pathogenic according to our data. Variant chr9-134834996-A-AC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 519656.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL5A1NM_000093.5 linkuse as main transcriptc.5165dup p.Val1723CysfsTer55 frameshift_variant 65/66 ENST00000371817.8 NP_000084.3
LOC101448202NR_103451.2 linkuse as main transcriptn.71-14788_71-14787insG intron_variant, non_coding_transcript_variant
COL5A1NM_001278074.1 linkuse as main transcriptc.5165dup p.Val1723CysfsTer55 frameshift_variant 65/66 NP_001265003.1
COL5A1XM_017014266.3 linkuse as main transcript downstream_gene_variant XP_016869755.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL5A1ENST00000371817.8 linkuse as main transcriptc.5165dup p.Val1723CysfsTer55 frameshift_variant 65/661 NM_000093.5 ENSP00000360882 P4P20908-1
COL5A1ENST00000371820.4 linkuse as main transcriptc.5165dup p.Val1723CysfsTer55 frameshift_variant 65/662 ENSP00000360885 A2P20908-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsSep 12, 2017The c.5165dupC variant, located in coding exon 65 of the COL5A1 gene, results from a duplication of C at nucleotide position 5165, causing a translational frameshift with a predicted alternate stop codon (p.V1723Cfs*55). The stop codon occurs at the 3' terminus of COL5A1 and is not expected to trigger nonsense-mediated mRNA decay. However, this alteration affect the significant portion of the C-terminal domain, which is generally known to be involved in Collagen trimer formation and folding (Chessler SD et al. J. Biol. Chem., 1993 Aug;268:18218-25; Lees JF et al. J. Biol. Chem., 1994 Sep;269:24354-60; McIntosh I et al. Hum. Mutat., 1995;5:121-5). In addition, COL5A1 variants downstream of this alteration have been reported in individuals with classic Ehlers Danlos syndrome, further supporting the importance of the C-terminus impacted by this alteration (Mitchell AL et al. Hum. Mutat., 2009 Jun;30:995-1002; Symoens S et al. Hum. Mutat., 2012 Oct;33:1485-93). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1554726251; hg19: chr9-137726842; API