NM_000093.5:c.4126dupT

Variant names:

• chr9-134817028-A-AT
• rs1131691820
• NM_000093.5:c.4126dupT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000093.5(COL5A1):​c.4126dupT​(p.Ser1376PhefsTer7) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. S1376S) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL5A1 NM_000093.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 3.38
• Publications: 1 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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 9-134817028-A-AT is Pathogenic according to our data. Variant chr9-134817028-A-AT is described in ClinVar as Pathogenic. ClinVar VariationId is 430182.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.4126dupT	p.Ser1376PhefsTer7	frameshift_variant	Exon 53 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4126dupT	p.Ser1376PhefsTer7	frameshift_variant	Exon 53 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.4126dupT	p.Ser1376PhefsTer7	frameshift_variant	Exon 53 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4126dupT	p.Ser1376PhefsTer7	frameshift_variant	Exon 53 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4126dupT	p.Ser1376PhefsTer7	frameshift_variant	Exon 53 of 66	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:1

May 23, 2017

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Although the c.4126dupT pathogenic variant in the COL5A1 gene has not been reported to our knowledge, this variant causes a shift in reading frame starting at codon Serine 1376, changing it to a Phenylalanine, and creating a premature stop codon at position 7 of the new reading frame, denoted p.Ser1376PhefsX7. This pathogenic variant is expected to result in either an abnormal, truncated protein product or loss of protein from this allele through nonsense-mediated mRNA decay. Multiple other frameshift variants in the COL5A1 gene have been reported in the Human Gene Mutation Database in association with classical Ehlers-Danlos syndrome (cEDS, EDS type I and II) (Stenson et al., 2014), indicating that loss of function is a mechanism of disease for this gene. Furthermore, the c.4126dupT variant has not been observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). -

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

Apr 18, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Loss-of-function variants in COL5A1 are known to be pathogenic (PMID: 23587214). For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals with COL5A1-related disease. ClinVar contains an entry for this variant (Variation ID: 430182). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser1376Phefs*7) in the COL5A1 gene. It is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.4
Mutation Taster		=3/197	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1131691820; hg19: chr9-137708874;