rs786200923

Variant names:

• chr9-134835204-TGTGA-T
• rs786200923
• NM_000093.5:c.5370+3_5370+6delGAGT

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000093.5(COL5A1):​c.5370+3_5370+6delGAGT variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 splice_region, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.51
• Publications: 0 publications found

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]

COL5A1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 9-134835204-TGTGA-T is Pathogenic according to our data. Variant chr9-134835204-TGTGA-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 17184.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.5370+3_5370+6delGAGT		splice_region_variant, intron_variant	Intron 65 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.5370+3_5370+6delGAGT		splice_region_variant, intron_variant	Intron 65 of 65		NP_001265003.1
LOC101448202	NR_103451.2	n.71-14999_71-14996delTCAC		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.5370+1_5370+4delGTGA		splice_donor_variant, splice_region_variant, intron_variant	Intron 65 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.5370+1_5370+4delGTGA		splice_donor_variant, splice_region_variant, intron_variant	Intron 65 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 33

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1 Pathogenic:2

Nov 01, 1996

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 02, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 65, but is expected to preserve the integrity of the reading-frame (PMID: 8923000). ClinVar contains an entry for this variant (Variation ID: 17184). This variant has been observed in individuals with Ehlers-Danlos syndrome, classical type (PMID: 8923000; Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 65 of the COL5A1 gene. It does not directly change the encoded amino acid sequence of the COL5A1 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Jan 17, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5370+3_5370+6delGAGT intronic variant begins 3 nucleotide after coding exon 65 in the COL5A1 gene. This variant results from a deletion of 4 nucleotides at positions c.5370+3 to c.5370+6. This variant was identified in one or more individuals with features consistent with COL5A1-related classic Ehlers-Danlos syndrome and segregated with disease in at least one family (Wenstrup RJ et al. Hum. Mol. Genet. 1996 Nov;5(11):1733-6). RNA studies demonstrated that this alteration results in abnormal splicing (Wenstrup RJ et al. Hum. Mol. Genet. 1996 Nov;5(11):1733-6). This nucleotide region is conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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
PhyloP100		9.5
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: 0

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

Other links and lift over

dbSNP: rs786200923; hg19: chr9-137727050;