rs1554726251

Positions:

• chr9-134834996-A-AC

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000093.5(COL5A1):​c.5165dupC​(p.Val1723fs) 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
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.15

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]

LOC101448202 (HGNC:):

ACMG classification

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
COL5A1	NM_000093.5	c.5165dupC	p.Val1723fs	frameshift_variant	65/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.5165dupC	p.Val1723fs	frameshift_variant	65/66		NP_001265003.1
LOC101448202	NR_103451.2	n.71-14788dupG		intron_variant
COL5A1	XM_017014266.3	c.*2243_*2244insC		downstream_gene_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.5165dupC	p.Val1723fs	frameshift_variant	65/66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.5165dupC	p.Val1723fs	frameshift_variant	65/66	2		ENSP00000360885.4

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

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2017

The 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

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

Other links and lift over

dbSNP: rs1554726251; hg19: chr9-137726842;