9-134801982-GC-GCCC

Variant names:

• chr9-134801982-G-GCC
• NM_000093.5:c.2987_2988dupCC

Variant summary

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

The NM_000093.5(COL5A1):​c.2987_2988dupCC​(p.Gly997ProfsTer78) 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A1 NM_000093.5 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -7.85

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]

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 9-134801982-G-GCC is Pathogenic according to our data. Variant chr9-134801982-G-GCC is described in ClinVar as [Pathogenic]. Clinvar id is 1798449.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.2987_2988dupCC	p.Gly997ProfsTer78	frameshift_variant	Exon 38 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.2987_2988dupCC	p.Gly997ProfsTer78	frameshift_variant	Exon 38 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.2987_2988dupCC	p.Gly997ProfsTer78	frameshift_variant	Exon 38 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.2987_2988dupCC	p.Gly997ProfsTer78	frameshift_variant	Exon 38 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.2987_2988dupCC	p.Gly997ProfsTer78	frameshift_variant	Exon 38 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jan 19, 2018

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2987_2988dupCC pathogenic mutation, located in coding exon 38 of the COL5A1 gene, results from a duplication of CC at nucleotide position 2987, causing a translational frameshift with a predicted alternate stop codon (p.G997Pfs*78). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-137693828;