Submissions for variant NM_001852.4(COL9A2):c.217C>T (p.Pro73Ser)

gnomAD frequency: 0.00012  dbSNP: rs375150574

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001528017	SCV001739175	likely benign	not provided	2020-03-16	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV001528017	SCV002283074	uncertain significance	not provided	2025-01-23	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 73 of the COL9A2 protein (p.Pro73Ser). This variant is present in population databases (rs375150574, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with COL9A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 1174415). 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 not expected to disrupt COL9A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003487428	SCV004241616	uncertain significance	not specified	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: COL9A2 c.217C>T (p.Pro73Ser) results in a non-conservative amino acid change located in the Collagen triple helix repeat (IPR008160) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.5e-05 in 1614236 control chromosomes (i.e., 72 alleles) in the gnomAD v4 database, including 2 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance, although are not suggestive of a variant associated with highly penetrant autosomal recessive or dominant disease. To our knowledge, no occurrence of c.217C>T in individuals affected with Epiphyseal dysplasia, multiple, 2 and no experimental evidence demonstrating its impact on protein function have been reported. Two submitters have reported clinical-significance assessments for this variant to ClinVar after 2014. One submitter classified the variant as likely benign, and one submitter classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
CeGaT Center for Human Genetics Tuebingen	RCV001528017	SCV004698472	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	COL9A2: BS2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004789658	SCV005399308	uncertain significance	Stickler syndrome, type 5	2020-05-25	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_001852.3(COL9A2):c.217C>T in exon 4 of 32 of the COL9A2 gene. This substitution is predicted to create a moderate amino acid change from proline to serine at position 73 of the protein, NP_001843.1(COL9A2):p.(Pro73Ser). The proline at this position has low conservation (100 vertebrates, UCSC), but is located within the collagen triple helix repeat region. In silico software predictions of the pathogenicity of this variant are conflicting (Polyphen, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a frequency of 0.0039% (11 heterozygotes, 0 homozygotes). The variant has not been previously reported in a clinical testing setting. Based on information available at the time of curation, this variant has been classified as a VARIANT of UNCERTAIN SIGNIFICANCE (VUS).
PreventionGenetics, part of Exact Sciences	RCV004741029	SCV005355981	uncertain significance	COL9A2-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The COL9A2 c.217C>T variant is predicted to result in the amino acid substitution p.Pro73Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.035% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.