Submissions for variant NM_000088.4(COL1A1):c.1042G>A (p.Ala348Thr)

gnomAD frequency: 0.00023  dbSNP: rs139955975

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000029552	SCV000052204	uncertain significance	not specified	2018-02-28	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000262664	SCV000404185	uncertain significance	Infantile cortical hyperostosis	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000320157	SCV000404186	uncertain significance	Ehlers-Danlos syndrome, arthrochalasia type	2017-04-27	criteria provided, single submitter	clinical testing	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.
Illumina Laboratory Services, Illumina	RCV000367913	SCV000404187	uncertain significance	Osteogenesis imperfecta	2017-04-27	criteria provided, single submitter	clinical testing	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.
GeneDx	RCV000521409	SCV000618069	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	Identified in two patients with TAAD in published literature, however, one individual also harbored a pathogenic variant in the FBN1 gene (Weerakkody et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; 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); This variant is associated with the following publications: (PMID: 29543232)
Invitae	RCV000560142	SCV000627159	likely benign	Osteogenesis imperfecta type I	2024-01-20	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000521409	SCV000857101	uncertain significance	not provided	2017-10-02	criteria provided, single submitter	clinical testing
Johns Hopkins Genomics, Johns Hopkins University	RCV000560142	SCV001430618	uncertain significance	Osteogenesis imperfecta type I	2020-07-22	criteria provided, single submitter	clinical testing	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.
Mayo Clinic Laboratories, Mayo Clinic	RCV000521409	SCV001715210	uncertain significance	not provided	2019-07-08	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV000367913	SCV002565116	uncertain significance	Osteogenesis imperfecta	2020-03-01	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002276573	SCV002565462	uncertain significance	Ehlers-Danlos syndrome	2020-03-01	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002399337	SCV002709682	uncertain significance	Cardiovascular phenotype	2023-08-30	criteria provided, single submitter	clinical testing	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.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000521409	SCV004565062	uncertain significance	not provided	2023-10-09	criteria provided, single submitter	clinical testing	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.
Centre for Genomic and Experimental Medicine, University of Edinburgh	RCV000599940	SCV000731244	likely pathogenic	Familial thoracic aortic aneurysm and aortic dissection		no assertion criteria provided	research