Submissions for variant NM_001852.4(COL9A2):c.682C>T (p.Pro228Ser)

gnomAD frequency: 0.00005  dbSNP: rs370064150

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV001563473	SCV001786423	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 has a deleterious effect on protein structure/function
Labcorp Genetics (formerly Invitae), Labcorp	RCV001563473	SCV002153463	uncertain significance	not provided	2024-01-14	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 228 of the COL9A2 protein (p.Pro228Ser). This variant is present in population databases (rs370064150, gnomAD 0.04%). 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: 1199096). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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	RCV003487490	SCV004241615	uncertain significance	not specified	2023-12-22	criteria provided, single submitter	clinical testing	Variant summary: COL9A2 c.682C>T (p.Pro228Ser) 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. In addition, this variant disrupts the third-to-last nucleotide of exon 13, and therefore can affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4.6e-05 in 1567114 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.682C>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	RCV001563473	SCV004698471	likely benign	not provided	2024-01-01	criteria provided, single submitter	clinical testing	COL9A2: BP4, BS2
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004785279	SCV005400135	uncertain significance	Stickler syndrome, type 5	2020-05-21	criteria provided, single submitter	clinical testing	A heterozygous missense variant was identified, NM_001852.3(COL9A2):c.682C>T in exon 13 of 32 of the COL9A2 gene. This substitution is predicted to create a moderate amino acid change from proline to serine at position 228 of the protein, NP_001843.1(COL9A2):p.(Pro228Ser), and may cause a splice site change leading to aberrant splicing. Further testing via RNA studies are required to confirm if splicing is altered. The proline at this position has moderate conservation (100 vertebrates, UCSC), and 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). In silico software does not predict this variant to cause aberrant splicing (NetGene2, Fruit fly, Human Splicing Finder). The variant is present in the gnomAD population database at a frequency of 0.0052% (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). Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
PreventionGenetics, part of Exact Sciences	RCV004741036	SCV005356657	uncertain significance	COL9A2-related disorder	2024-03-27	no assertion criteria provided	clinical testing	The COL9A2 c.682C>T variant is predicted to result in the amino acid substitution p.Pro228Ser. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.048% 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.