ClinVar Miner

Submissions for variant NM_001851.6(COL9A1):c.1634G>A (p.Arg545His)

gnomAD frequency: 0.00025  dbSNP: rs145698301
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000344967 SCV000334750 uncertain significance not provided 2015-09-16 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV000764653 SCV000895776 uncertain significance Epiphyseal dysplasia, multiple, 6; Stickler syndrome, type 4 2018-10-31 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000344967 SCV001420252 likely benign not provided 2024-12-10 criteria provided, single submitter clinical testing
GeneDx RCV000344967 SCV002007366 uncertain significance not provided 2025-01-14 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
Ambry Genetics RCV002518868 SCV003744146 uncertain significance Inborn genetic diseases 2022-12-21 criteria provided, single submitter clinical testing The c.1634G>A (p.R545H) alteration is located in exon 24 (coding exon 24) of the COL9A1 gene. This alteration results from a G to A substitution at nucleotide position 1634, causing the arginine (R) at amino acid position 545 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Department of Pathology and Laboratory Medicine, Sinai Health System RCV000344967 SCV001553758 uncertain significance not provided no assertion criteria provided clinical testing The COL9A1 p.R545H variant was not identified in the literature nor was it identified in LOVD 3.0, however it was identified in dbSNP (ID: rs145698301) and in ClinVar (classified as uncertain significance by EGL Genetic Diagnostics and Fulgent Genetics for Stickler syndrome type 4 and Multiple epiphyseal dysplasia 6). The variant was identified in control databases in 38 of 282812 chromosomes at a frequency of 0.0001344 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: African in 20 of 24964 chromosomes (freq: 0.000801), European (non-Finnish) in 14 of 129152 chromosomes (freq: 0.000108), South Asian in 2 of 30610 chromosomes (freq: 0.000065) and Latino in 2 of 35426 chromosomes (freq: 0.000056), but was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), or Other populations. The p.Arg545 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. 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. 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.

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