ClinVar Miner

Submissions for variant NM_000091.4(COL4A3):c.88-4C>T (rs148393022)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000246764 SCV000717817 benign not specified 2017-09-20 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Illumina Clinical Services Laboratory,Illumina RCV000325981 SCV000428142 likely benign Alport syndrome 2016-06-14 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000246764 SCV000917262 benign not specified 2018-10-29 criteria provided, single submitter clinical testing Variant summary: COL4A3 c.88-4C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.016 in 277078 control chromosomes, predominantly at a frequency of 0.11 within the Latino subpopulation in the gnomAD database, including 235 homozygotes. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 54-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL4A3 causing autosomal recessive Alport Syndrome (0.002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. To our knowledge, no occurrence of c.88-4C>T in individuals affected with autosomal recessive Alport Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (3x) /likely benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000246764 SCV000711866 benign not specified 2016-03-21 criteria provided, single submitter clinical testing c.88-4C>T in intron 1 of COL4A3: This variant is not expected to have clinical s ignificance because it is not located within the splice consensus sequence and h as been identified in 11.92% (1380/11576) of Latino chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs148393022).
PreventionGenetics RCV000246764 SCV000302088 benign not specified 2016-04-20 criteria provided, single submitter clinical testing

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