ClinVar Miner

Submissions for variant NM_004370.6(COL12A1):c.3652G>A (p.Val1218Met)

gnomAD frequency: 0.00011  dbSNP: rs201749138
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000945934 SCV001092009 likely benign Ullrich congenital muscular dystrophy 2; Bethlem myopathy 2 2023-12-21 criteria provided, single submitter clinical testing
GeneDx RCV001593138 SCV001823497 likely benign not provided 2020-07-17 criteria provided, single submitter clinical testing
Revvity Omics, Revvity RCV001593138 SCV003833388 uncertain significance not provided 2021-12-10 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System RCV001356650 SCV001551877 benign not specified no assertion criteria provided clinical testing The COL12A1 p.Val1218Met variant was not identified in the literature nor was it identified in ClinVar. The variant was identified in dbSNP (ID: rs201749138), Cosmic (FATHMM prediction: pathogenic; score=0.79) and LOVD 3.0 (classified as likely benign). The variant was identified in control databases in 95 of 280420 chromosomes at a frequency of 0.000339 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 81 of 19490 chromosomes (freq: 0.004156), Latino in 6 of 35270 chromosomes (freq: 0.00017), European (non-Finnish) in 7 of 128376 chromosomes (freq: 0.000055) and South Asian in 1 of 30590 chromosomes (freq: 0.000033), but not in the African, Ashkenazi Jewish, European (Finnish), and Other populations. The p.Val1218 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 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.

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