rs139955975

Positions:

• chr17-50195937-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000088.4(COL1A1):​c.1042G>A​(p.Ala348Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000451 in 1,588,628 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (0 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:13 B:1
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
• BS2: High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1042G>A	p.Ala348Thr	missense_variant	16/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.1042G>A	p.Ala348Thr	missense_variant	16/49		XP_005257115.2
COL1A1	XM_005257059.5	c.957+377G>A		intron_variant			XP_005257116.2
COL1A1	XM_011524341.2	c.957+377G>A		intron_variant			XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1042G>A	p.Ala348Thr	missense_variant	16/51	1	NM_000088.4	ENSP00000225964	P1

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000484

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000426

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000129 AC: 27 AN: 209234 Hom.: 0 AF XY: 0.000125 AC XY: 14 AN XY: 111810

Gnomad AFR exome AF: 0.000157

Gnomad AMR exome AF: 0.00

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: 0.000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000476 AC: 684 AN: 1436598 Hom.: 0 Cov.: 33 AF XY: 0.000466 AC XY: 332 AN XY: 711872

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000247

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000570

Gnomad4 OTH exome AF: 0.000924

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152030 Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11 AN XY: 74266

Gnomad4 AFR AF: 0.0000484

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000437 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:13 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 08, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 17, 2024	Identified in two patients with thoracic aortic aneurysm and dissection (TAAD) in published literature, however, one individual also harbored a pathogenic variant in the FBN1 gene (PMID: 29543232); Occurs in the triple helical domain at the X 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 X position is not a common mechanism of disease (HGMD); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29543232) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 02, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 09, 2023	The COL1A1 c.1042G>A; p.Ala348Thr variant (rs139955975) is reported in the literature in two individuals affected with thoracic aortic aneurysm or dissection (Weerakkody 2018). This variant is reported in ClinVar (Variation ID: 35897) and is found in the non-Finnish European population with an allele frequency of 0.028% (30/107,172 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.329). While this variant occurs in the Gly-X-Y triple helix repeat domain, it does not alter a conserved glycine reside like the majority of disease-causing missense variants (Amor Ben 2011). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Ben Amor I et al. Genotype-phenotype correlations in autosomal dominant osteogenesis imperfecta. J Osteoporos. 2011; 2011:540178. PMID: 21912751 Weerakkody R et al. Targeted genetic analysis in a large cohort of familial and sporadic cases of aneurysm or dissection of the thoracic aorta. Genet Med. 2018 Nov;20(11):1414-1422. PMID: 29543232. -

Osteogenesis imperfecta Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Osteogenesis imperfecta type I Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 20, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jul 22, 2020	This variant has been reported in an individual presenting with aneurysm. This COL1A1 variant (rs139955975) is rare (<0.1%) in a large population dataset (gnomAD: 33/240566 total alleles; 0.01%; no homozygotes), and has been reported in ClinVar. Three bioinformatic tools queried predict that this substitution would be tolerated, and the alanine residue at this position is evolutionarily conserved across mammals. We consider the clinical significance of c.1042G>A to be uncertain at this time. -

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Centre for Genomic and Experimental Medicine, University of Edinburgh

-

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Feb 28, 2018

Variant summary: COL1A1 c.1042G>A (p.Ala348Thr) results in a non-conservative amino acid change located in the Collagen triple helix repeat of the encoded protein sequence. Although A348T does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL1A1 gene, where the majority of pathogenic missense variants occur. At-least three of five in-silico tools evaluated predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00027 in 36540 control chromosomes. The observed variant frequency is approximately 9.73 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05). However, only 10 occurrences were found in controls, which is too low to make a conclusion. To our knowledge, no occurrence of c.1042G>A in individuals affected with Osteogenesis Imperfecta and no experimental evidence demonstrating its impact on protein function have been reported. At-least one internal co-occurrence with other pathogenic variant(s) have been reported (COL1A2 c.639+2T>G), providing supporting evidence for a benign role. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Mar 01, 2020

- -

COL1A1-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 13, 2024

The COL1A1 c.1042G>A variant is predicted to result in the amino acid substitution p.Ala348Thr. This variant was previously reported in a cohort of individuals with aneurysm or dissection of the thoracic aorta (Weerakkody et al. 2018. PubMed ID: 2954332). This variant is reported in 0.028% of alleles in individuals of European (Non-Finnish) descent in gnomAD. However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Ehlers-Danlos syndrome, arthrochalasia type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Infantile cortical hyperostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 30, 2023

The p.A348T variant (also known as c.1042G>A), located in coding exon 16 of the COL1A1 gene, results from a G to A substitution at nucleotide position 1042. The alanine at codon 348 is replaced by threonine, an amino acid with similar properties. This variant was reported in two individuals with thoracic aortic aneurysm or dissection (Weerakkody R et al. Genet. Med., 2018 11;20:1414-1422). This alteration has also been noted in a biobank cohort (Wright CF et al. Am J Hum Genet, 2019 Feb;104:275-286). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Uncertain	0.66	D
MutationTaster	Benign	0.53	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.070	T
Sift4G	Benign	0.44	T
Vest4		0.60
MVP		0.79
MPC		0.54
ClinPred		0.18	T
GERP RS		4.5
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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

Other links and lift over

dbSNP: rs139955975; hg19: chr17-48273298;