ClinVar Miner

Submissions for variant NM_000092.4(COL4A4):c.2638del (p.Ala880fs) (rs778043831)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000665226 SCV000789309 pathogenic Alport syndrome, autosomal recessive 2017-01-27 criteria provided, single submitter clinical testing
Invitae RCV001245708 SCV001419011 pathogenic not provided 2019-11-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Ala880Hisfs*70) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs778043831, ExAC 0.02%). This variant has been observed in individual(s) with Alport syndrome (PMID: 24052634, 12325029, 17216251). This variant is also known as 2864delG in the literature. ClinVar contains an entry for this variant (Variation ID: 550471). Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 19129241, 21196518, 24052634, 24522496, 24854265, 25307543, 26809805, 27281700). For these reasons, this variant has been classified as Pathogenic.
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001251490 SCV001427145 pathogenic Benign familial hematuria 2018-09-19 criteria provided, single submitter clinical testing A heterozygous frameshift deletion variant, NM_000092.4(COL4A4):c.2638delG, has been identified in exon 30 of 48 of the COL4A4 gene. This deletion is predicted to create a frameshift starting at amino acid position 880, introducing a stop codon 70 residues downstream (NP_000083.3(COL4A4):p.(Ala880Hisfs*70)). This variant is predicted to result in loss of protein function through nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. However, truncation of the protein (including the loss of half the triple-helical region and both C4 domains) as a result of a NMD-escape mechanism has not been excluded. The variant is present in the gnomAD database at a frequency of 0.001% (3 heterozygotes, 0 homozygotes). The variant has been previously described as pathogenic in multiple patients, in either homozygous or compound heterozygous state, with Alport syndrome (ClinVar; Storey, H. et al., 2013; Dagher, H. et al., 2002). In addition, several different variants downstream, predicted to cause NMD, have also been reported pathogenic in patients with Alport Syndrome (ClinVar, HGMD). Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.

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