rs140950220

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_032888.4(COL27A1):c.2089G>C(p.Gly697Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000576 in 1,614,062 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.00032 ( 1 hom., cov: 33)

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

COL27A1
NM_032888.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 6.17

Variant links:

Genes affected

COL27A1 (HGNC:22986): (collagen type XXVII alpha 1 chain) This gene encodes a member of the fibrillar collagen family, and plays a role during the calcification of cartilage and the transition of cartilage to bone. The encoded protein product is a preproprotein. It includes an N-terminal signal peptide, which is followed by an N-terminal propetide, mature peptide and a C-terminal propeptide. The N-terminal propeptide contains thrombospondin N-terminal-like and laminin G-like domains. The mature peptide is a major triple-helical region. The C-terminal propeptide, also known as COLFI domain, plays crucial roles in tissue growth and repair. Mutations in this gene cause Steel syndrome. Alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Sep 2014]

COL27A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.817

PP5

Variant 9-114195977-G-C is Pathogenic according to our data. Variant chr9-114195977-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 143245.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-114195977-G-C is described in Lovd as [Pathogenic]. Variant chr9-114195977-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4 link	c.2089G>C	p.Gly697Arg	missense_variant	Exon 7 of 61	ENST00000356083.8	NP_116277.2	Q8IZC6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL27A1	ENST00000356083.8 link	c.2089G>C	p.Gly697Arg	missense_variant	Exon 7 of 61	1	NM_032888.4	ENSP00000348385.3	Q8IZC6-1
COL27A1	ENST00000451716.5 link	c.1876G>C	p.Gly626Arg	missense_variant	Exon 4 of 8	1		ENSP00000391328.1	Q5T1U7
COL27A1	ENST00000494090.6 link	n.982G>C		non_coding_transcript_exon_variant	Exon 4 of 58	1		ENSP00000432928.1	H0YD40

Frequencies

GnomAD3 genomes

AF:

0.000315

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251432

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135892

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000308

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000581

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000315

AC:

AN:

152324

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.000759

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Steel syndrome

Pathogenic:5

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 29, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL27A1 c.2089G>C (p.Gly697Arg) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence and disrupts a Gly residue at position 1 of a Gly-X-Y motif. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 396206 control chromosomes, predominantly at a frequency of 0.00096 within the Latino subpopulation in the gnomAD database, including 1 homozygote (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although studies have demonstrated that the variant of interest likely represents a founder mutation in individuals of Puerto Rican descent and that Steel syndrome can go undiagnosed (e.g., Belbin_2017). c.2089G>C has been reported in the literature in multiple homozygous individuals affected with Steel syndrome, primarily those of Puerto Rican or Hispanic/Latino descent (e.g., Gonzaga_Jauregui_2015, Belbin_2017). Additionally, individuals harboring the variant in the heterozygous state were reported to display an increased incidence of milder forms of musculoskeletal disease, including joint and spine degeneration, than non-carriers (e.g., Belbin_2017). These data indicate that the variant is very likely to be associated with autosomal recessive disease, but could lead to mild symptoms in heterozygous individuals as well. At least one publication reports experimental evidence evaluating an impact on protein function, finding that a murine model of the variant recapitulates many Steel-syndrome associated features (e.g., Gonzaga-Jauregui_2020). The following publications have been ascertained in the context of this evaluation (PMID: 28895531, 24986830, 32376988). Four submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Jul 02, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jul 02, 2014

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

Segregates with the phenotype in an affected family -

Feb 01, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Pathogenic:2

Mar 16, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate the variant causes abnormal collagen deposition in the extracellular matrix (Gonzaga-Jauregui et el., 2020); This variant is associated with the following publications: (PMID: 24986830, 31903681, 32376988, 28895531) -

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 697 of the COL27A1 protein (p.Gly697Arg). This variant is present in population databases (rs140950220, gnomAD 0.01%). This missense change has been observed in individuals with Steel syndrome (PMID: 24986830, 31903681). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 143245). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt COL27A1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

COL27A1-related disorder

Pathogenic:1

Jul 08, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The COL27A1 c.2089G>C variant is predicted to result in the amino acid substitution p.Gly697Arg. This variant has been reported in the homozygous state in several individuals with Steel syndrome and is a well-documented as a founder variant in individuals of Puerto Rican ancestry (see for example, Gonzaga-Jauregui et al 2015. PubMed ID: 24986830; Belbin et al 2017. PubMed ID: 28895531; Amlie-Wolf et al 2020. PubMed ID: 31903681; Gonzaga-Jauregui et al 2020. PubMed ID: 32376988). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.71

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.59

D;D

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

M_CAP

Pathogenic

0.88

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.0

H;.

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Pathogenic

0.97

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.95

Gain of MoRF binding (P = 0.0156);.;

MVP

0.83

MPC

0.13

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.90

gMVP

0.92

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over