9-134823426-GCCCGA-G

Position:

• chr9-134823426-GCCCGA-G

Variant summary

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

The NM_000093.5(COL5A1):​c.4656_4660del​(p.Pro1553GlyfsTer2) variant causes a frameshift change involving the alteration of a 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. G1552G) 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, single submitter P:1
• Conservation: PhyloP100: 7.25

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 9-134823426-GCCCGA-G is Pathogenic according to our data. Variant chr9-134823426-GCCCGA-G is described in ClinVar as [Pathogenic]. Clinvar id is 459702.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.4656_4660del	p.Pro1553GlyfsTer2	frameshift_variant	61/66	ENST00000371817.8
LOC101448202	NR_103451.2	n.71-3222_71-3218del		intron_variant, non_coding_transcript_variant
COL5A1	NM_001278074.1	c.4656_4660del	p.Pro1553GlyfsTer2	frameshift_variant	61/66
COL5A1	XM_017014266.3	c.4656_4660del	p.Pro1553GlyfsTer2	frameshift_variant	61/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.4656_4660del	p.Pro1553GlyfsTer2	frameshift_variant	61/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.4656_4660del	p.Pro1553GlyfsTer2	frameshift_variant	61/66	2		A2
COL5A1	ENST00000460264.5	n.124_128del		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes Cov.: 34

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

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2017

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in COL5A1 are known to be pathogenic (PMID: 23587214). This sequence change deletes 5 nucleotides from exon 61 of the COL5A1 mRNA (c.4656_4660delCCCGA), causing a frameshift at codon 1553. This creates a premature translational stop signal (p.Pro1553Glyfs*2) and is expected to result in an absent or disrupted protein product. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554807812; hg19: chr9-137715272;