9-134825849-G-T

Variant names:

• chr9-134825849-G-T
• NM_000093.5:c.5012G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000093.5(COL5A1):​c.5012G>T​(p.Cys1671Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.83

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.5012G>T	p.Cys1671Phe	missense_variant	Exon 63 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.5012G>T	p.Cys1671Phe	missense_variant	Exon 63 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.5012G>T	p.Cys1671Phe	missense_variant	Exon 63 of 65		XP_016869755.1
LOC101448202	NR_103451.2	n.71-5640C>A		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.5012G>T	p.Cys1671Phe	missense_variant	Exon 63 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.5012G>T	p.Cys1671Phe	missense_variant	Exon 63 of 66	2		ENSP00000360885.4
COL5A1	ENST00000460264.5	n.480G>T		non_coding_transcript_exon_variant	Exon 4 of 5	3
COL5A1	ENST00000465877.1	n.192G>T		non_coding_transcript_exon_variant	Exon 2 of 4	3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Apr 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C1671F variant (also known as c.5012G>T), located in coding exon 63 of the COL5A1 gene, results from a G to T substitution at nucleotide position 5012. The cysteine at codon 1671 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

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

Oct 08, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with Ehlers-Danlos syndrome, classical type (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 1671 of the COL5A1 protein (p.Cys1671Phe). ClinVar contains an entry for this variant (Variation ID: 1437556). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL5A1 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.47	D
BayesDel_noAF	Pathogenic	0.44
CADD	Pathogenic	28
DANN	Benign	0.97
DEOGEN2	Uncertain	0.69	D;.
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	H;H
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-9.3	D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0020	D;D
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.90		Gain of phosphorylation at Y1670 (P = 0.1551);Gain of phosphorylation at Y1670 (P = 0.1551);
MVP		0.95
MPC		0.45
ClinPred		1.0	D
GERP RS		4.0
Varity_R		0.97
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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: chr9-137717695;