rs1554726283

Variant names:

• chr9-134835149-AG-A
• rs1554726283
• NM_000093.5:c.5317delG

Variant summary

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

The NM_000093.5(COL5A1):​c.5317delG​(p.Glu1773ArgfsTer94) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.13

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 9-134835149-AG-A is Pathogenic according to our data. Variant chr9-134835149-AG-A is described in ClinVar as [Pathogenic]. Clinvar id is 529240.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.5317delG	p.Glu1773ArgfsTer94	frameshift_variant	Exon 65 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.5317delG	p.Glu1773ArgfsTer94	frameshift_variant	Exon 65 of 66		NP_001265003.1
LOC101448202	NR_103451.2	n.71-14941delC		intron_variant	Intron 1 of 1
COL5A1	XM_017014266.3	c.*2397delG		downstream_gene_variant			XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.5317delG	p.Glu1773ArgfsTer94	frameshift_variant	Exon 65 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.5317delG	p.Glu1773ArgfsTer94	frameshift_variant	Exon 65 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1 Pathogenic:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 529240). For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the COL5A1 protein in which other variant(s) (p.Gln1809*) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change results in a frameshift in the COL5A1 gene (p.Glu1773Argfs*94). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 66 amino acid(s) of the COL5A1 protein and extend the protein by 27 additional amino acid residues. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554726283; hg19: chr9-137726995;