rs1060502247

Positions:

• chr9-134811493-GA-AT

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000093.5(COL5A1):​c.3584_3585delinsAT​(p.Gly1195Asp) variant causes a missense, splice region 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL5A1 NM_000093.5 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.81

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A1. . Gene score misZ 2.0682 (greater than the threshold 3.09). Trascript score misZ 4.1823 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 1, arterial disorder, Ehlers-Danlos syndrome, classic type.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.3584_3585delinsAT	p.Gly1195Asp	missense_variant, splice_region_variant	46/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.3584_3585delinsAT	p.Gly1195Asp	missense_variant, splice_region_variant	46/66		NP_001265003.1
COL5A1	XM_017014266.3	c.3584_3585delinsAT	p.Gly1195Asp	missense_variant, splice_region_variant	46/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.3584_3585delinsAT	p.Gly1195Asp	missense_variant, splice_region_variant	46/66	1	NM_000093.5	ENSP00000360882	P4
COL5A1	ENST00000371820.4	c.3584_3585delinsAT	p.Gly1195Asp	missense_variant, splice_region_variant	46/66	2		ENSP00000360885	A2

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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 08, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL5A1-related disease. In summary, this variant is a novel missense change that affects a glycine residue predicted to be important for COL5A1 protein function. However, the available evidence is currently insufficient to make a definite classification. Therefore, it has been classified as a Variant of Uncertain Significance. Glycine residues within the triple helix region are important for fibrillar collagens structure and stability (PMID: 7695699, 8218237, 19344236). In the case of COL5A1, missense substitutions affecting glycine residues are overrepressented among patients with Ehlers-Danlos syndrome (EDS) although the number of patients described so far is too limited to reach significance (PMID: 22696272, 23587214). This sequence change replaces glycine with aspartic acid at codon 1195 of the COL5A1 protein (p.Gly1195Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

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: rs1060502247; hg19: chr9-137703339;