ClinVar Miner

Submissions for variant NM_000419.5(ITGA2B):c.1374C>G (p.Ile458Met)

dbSNP: rs372294932
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen Platelet Disorders Variant Curation Expert Panel, ClinGen RCV003093980 SCV005061672 benign Glanzmann thrombasthenia 2024-04-16 reviewed by expert panel curation The NM_000419.5(ITGA2B):c.1374C>G (p.Ile458Met) missense variant has been reported in at least one patient (Patient 6 in PMID:19172520/GT database record 163), however it occurs at a high allele frequency with the highest population minor allele frequency in gnomAD v4.0.0 is 0.003502 (319/91084 alleles with 3 homozygotes) in the South Asian population, which is higher than the ClinGen PD VCEP threshold (>0.0024), and therefore meets this criterion (BA1). In summary, this variant meets the criteria to be classified as Benign, for autosomal recessive Glanzmann Thrombasthenia based on the ACMG/AMP criteria applied, as specified by the ClinGen PD VCEP: BA1 (VCEP specifications version 2.1).
Mendelics RCV002247906 SCV002517212 uncertain significance not specified 2022-05-04 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV003093980 SCV003264352 likely benign Glanzmann thrombasthenia 2022-11-23 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV002247906 SCV004028693 uncertain significance not specified 2023-07-05 criteria provided, single submitter clinical testing Variant summary: ITGA2B c.1374C>G (p.Ile458Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00046 in 251460 control chromosomes, predominantly at a frequency of 0.0037 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1374C>G has been reported in the literature in at least one homozygous individual affected with Glanzmann thrombasthenia 1 (e.g., Vijapurkar_2009, Mansour_2011). These reports do not provide unequivocal conclusions about association of the variant with Glanzmann thrombasthenia 1. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 21029361, 19172520). 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 uncertain significance.
Breakthrough Genomics, Breakthrough Genomics RCV004694195 SCV005192909 uncertain significance not provided criteria provided, single submitter not provided

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