Submissions for variant NM_000393.5(COL5A2):c.2117C>T (p.Pro706Leu)

gnomAD frequency: 0.00016  dbSNP: rs146175905

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV002231700	SCV000631576	likely benign	Ehlers-Danlos syndrome, classic type, 1	2023-12-26	criteria provided, single submitter	clinical testing
GeneDx	RCV001354120	SCV001770291	uncertain significance	not provided	2022-02-15	criteria provided, single submitter	clinical testing	Has been reported in an individual with congenital heart defects, who also harbored variants in several other genes (Jin et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28166811, 28991257, 27535533)
Ambry Genetics	RCV002420392	SCV002726016	uncertain significance	Familial thoracic aortic aneurysm and aortic dissection	2019-11-20	criteria provided, single submitter	clinical testing	The p.P706L variant (also known as c.2117C>T), located in coding exon 32 of the COL5A2 gene, results from a C to T substitution at nucleotide position 2117. The proline at codon 706 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with unspecified conotruncal defects who also carried the COL5A2 p.R1070H alteration (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601). This amino acid position is highly 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.
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000582800	SCV000692242	uncertain significance	Marfan syndrome	2016-12-30	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354120	SCV001548657	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL5A2 p.Pro706Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs146175905) and in ClinVar (classified as a VUS by Invitae and Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital). The variant was also identified in control databases in 28 of 282454 chromosomes at a frequency of 0.000099 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 14 of 24910 chromosomes (freq: 0.000562), Other in 1 of 7210 chromosomes (freq: 0.000139), South Asian in 4 of 30594 chromosomes (freq: 0.000131), Latino in 4 of 35382 chromosomes (freq: 0.000113) and European (non-Finnish) in 5 of 129032 chromosomes (freq: 0.000039); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Pro706 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.