ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.4421C>T (p.Thr1474Met)

gnomAD frequency: 0.00005  dbSNP: rs201615111
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Laboratory Services, Illumina RCV000407621 SCV000428069 uncertain significance Alport syndrome 2018-01-12 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx RCV001660696 SCV001875206 uncertain significance not provided 2023-03-29 criteria provided, single submitter clinical testing Reported as heterozygous in patients with focal segmental glomerulosclerosis in published literature who also harbored variants in other collagen genes (Wang et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30968591, 32703181, 32332277, 28476686, 31328266)
3billion RCV002283476 SCV002573136 pathogenic Autosomal recessive Alport syndrome 2022-09-01 criteria provided, single submitter clinical testing The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.015%). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL4A4-related disorder (PMID: 28476686). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 28476686 , 30968591 , 32332277 , 32703181). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children RCV002294291 SCV002587173 uncertain significance Kidney disorder 2019-08-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002504132 SCV002816780 uncertain significance Autosomal recessive Alport syndrome; Benign familial hematuria 2022-04-23 criteria provided, single submitter clinical testing
Invitae RCV001660696 SCV003522201 benign not provided 2024-01-04 criteria provided, single submitter clinical testing
Natera, Inc. RCV000407621 SCV002078861 uncertain significance Alport syndrome 2020-01-16 no assertion criteria provided clinical testing

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