Submissions for variant NM_000493.4(COL10A1):c.43T>G (p.Leu15Val)

gnomAD frequency: 0.00091  dbSNP: rs147612968

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000359455	SCV000459727	benign	Metaphyseal chondrodysplasia, Schmid type	2018-01-13	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Invitae	RCV000970841	SCV001118446	likely benign	not provided	2024-01-11	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000970841	SCV001551074	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL10A1 p.Leu15Val variant was not identified in the literature nor was it identified in the Cosmic or LOVD 3.0 databases. The variant was identified in dbSNP (ID: rs147612968) and ClinVar (classified as likely benign for metaphyseal chondrodysplasia by Illumina in 2016). The variant was identified in control databases in 97 of 282864 chromosomes at a frequency of 0.000343 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 83 of 24972 chromosomes (freq: 0.003324), Latino in 11 of 35438 chromosomes (freq: 0.00031) and European (non-Finnish) in 3 of 129170 chromosomes (freq: 0.000023); it was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Leu15 residue is not 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 3 of 4 in silico or computational prediction software programs (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.