Submissions for variant NM_001851.6(COL9A1):c.902C>T (p.Pro301Leu)

gnomAD frequency: 0.00083  dbSNP: rs192047082

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000991647	SCV001143285	uncertain significance	not provided	2018-08-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000991647	SCV001197802	likely benign	not provided	2025-01-22	criteria provided, single submitter	clinical testing
Department of Otolaryngology – Head & Neck Surgery, Cochlear Implant Center	RCV001375076	SCV001571893	uncertain significance	Hearing impairment	2021-04-12	criteria provided, single submitter	clinical testing	PP3_Supporting
GeneDx	RCV000991647	SCV001763966	uncertain significance	not provided	2024-10-28	criteria provided, single submitter	clinical testing	Previously reported in a female with infantile malignant osteopetrosis who also harbored a homozygous frameshift variant in the TCIRG1 gene (Zhang (2016) http:/www.jcp-sh.org.cn/EN/Y2016/V34/I1/43 ); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002278615	SCV002566398	uncertain significance	Connective tissue disorder	2020-04-01	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV003447524	SCV004175853	uncertain significance	Stickler syndrome, type 4	2023-03-01	criteria provided, single submitter	clinical testing	The missense c.902C>T(p.Pro301Leu) variant in COL9A1 gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Pro301Leu variant has been reported with allele frequency of 0.07% in gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance (multiple submissions). The amino acid change p.Pro301Leu in COL9A1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Pro at position 301 is changed to a Leu changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance (VUS).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004767244	SCV005381132	uncertain significance	not specified	2024-08-14	criteria provided, single submitter	clinical testing	Variant summary: COL9A1 c.902C>T (p.Pro301Leu) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00074 in 246936 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in COL9A1 causing COL9A1-Related Disorders, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.902C>T in individuals affected with COL9A1-Related Disorders and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 357811). Based on the evidence outlined above, the variant was classified as uncertain significance.
PreventionGenetics, part of Exact Sciences	RCV003950271	SCV004766610	likely benign	COL9A1-related disorder	2022-03-18	no assertion criteria provided	clinical testing	This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).