NM_000088.4:c.740C>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2

The NM_000088.4(COL1A1):c.740C>T(p.Pro247Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000293 in 1,613,640 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00029 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: 8.03

Publications

5 publications found

Variant links:

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A1 Gene-Disease associations (from GenCC):

Caffey disease
Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Ambry Genetics, ClinGen
Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome, arthrochalasia type
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
osteogenesis imperfecta type 1
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
osteogenesis imperfecta type 2
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
osteogenesis imperfecta type 3
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
osteogenesis imperfecta type 4
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
Ehlers-Danlos syndrome, classic type, 1
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
Ehlers-Danlos syndrome, classic type
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Ehlers-Danlos/osteogenesis imperfecta syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
high bone mass osteogenesis imperfecta
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

COL1A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000088.4

PP2

Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to high bone mass osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Caffey disease, osteogenesis imperfecta type 4, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos/osteogenesis imperfecta syndrome.

BP4

Computational evidence support a benign effect (MetaRNN=0.33784413).

BP6

Variant 17-50197190-G-A is Benign according to our data. Variant chr17-50197190-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287981.

BS2

High AC in GnomAd4 at 54 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL1A1	NM_000088.4 link	c.740C>T	p.Pro247Leu	missense_variant	Exon 10 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2 link	c.740C>T	p.Pro247Leu	missense_variant	Exon 10 of 48		XP_011522643.1
COL1A1	XM_005257058.5 link	c.740C>T	p.Pro247Leu	missense_variant	Exon 10 of 49		XP_005257115.2
COL1A1	XM_005257059.5 link	c.740C>T	p.Pro247Leu	missense_variant	Exon 10 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10 link	c.740C>T	p.Pro247Leu	missense_variant	Exon 10 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000495677.1 link	n.467C>T		non_coding_transcript_exon_variant	Exon 5 of 8	3

Frequencies

GnomAD3 genomes

AF:

0.000355

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00229

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:

0.000265

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000163

AC:

AN:

251448

AF XY:

0.000169

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000549

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000167

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000286

AC:

418

AN:

1461404

Hom.:

Cov.:

AF XY:

0.000279

AC XY:

203

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.0000598

AC:

AN:

33470

American (AMR)

AF:

0.000380

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5398

European-Non Finnish (NFE)

AF:

0.000341

AC:

379

AN:

1112004

Other (OTH)

AF:

0.000315

AC:

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

123

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000355

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41536

American (AMR)

AF:

0.00229

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67992

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000290

Hom.:

Bravo

AF:

0.000363

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000273

EpiControl

AF:

0.000296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

May 31, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL1A1: BS1 -

Aug 04, 2025

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in two brothers from one Spanish family, one diagnosed with mild autosomal recessive osteogenesis imperfecta and the other diagnosed with mild Bruck syndrome; however, this variant was also found in their unaffected father, and both brothers were also compound heterozygous for a splice site variant and a missense variant in the PLOD1 gene (PMID: 22689593); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat. Although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 25983617, 22689593) -

Ehlers-Danlos syndrome

Uncertain:1

Jun 14, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Sep 24, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL1A1 c.740C>T (p.Pro247Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251448 control chromosomes. The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05). c.740C>T has been reported in the literature in individuals affected with Osteogenesis Imperfecta. These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25983617). ClinVar contains an entry for this variant (Variation ID: 287981). Based on the evidence outlined above, the variant was classified as likely benign. -

COL1A1-related disorder

Benign:1

Jan 04, 2024

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Jan 26, 2021

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Osteogenesis imperfecta type I

Benign:1

Nov 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.83

M_CAP

Uncertain

0.26

MetaRNN

Benign

0.34

MetaSVM

Pathogenic

0.90

PhyloP100

8.0

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-4.3

REVEL

Uncertain

0.56

Sift

Benign

0.036

Sift4G

Uncertain

0.052

Vest4

0.39

MVP

0.85

MPC

0.57

ClinPred

0.22

GERP RS

4.9

gMVP

0.76

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over