ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.4129C>T (p.Arg1377Ter) (rs121912861)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Counsyl RCV000018950 SCV000797146 pathogenic Alport syndrome, autosomal recessive 2018-01-15 criteria provided, single submitter clinical testing
Victorian Clinical Genetics Services,Murdoch Childrens Research Institute RCV001251501 SCV001427120 pathogenic Benign familial hematuria 2018-06-28 criteria provided, single submitter clinical testing A heterozygous nonsense variant, NM_000092.4(COL4A4):c.4129C>T, has been identified in exon 44 of 48 of the COL4A4 gene. The variant is predicted to result in a premature stop codon at position 1377 of the protein, NP_000083.3(COL4A4):p.(Arg1377*). This variant is predicted to result in loss of protein function either through truncation (including loss of a quarter of the protein) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.00081% (2 heterozygotes, 0 homozygote). The variant has previously been described as pathogenic in multiple patients with Alport syndrome (ClinVar, Boye, E., et al. (1998), Buzza, M., et al. (2001), Buzza, M., et al. (2003)) and has also been shown to segregate with haematuria in these families. In addition, other truncating variants upstream and downstream of this variant have been reported as pathogenic in individuals with Alport sydrome. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Invitae RCV000681673 SCV001578221 pathogenic not provided 2020-08-25 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Arg1377*) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs121912861, ExAC 0.003%). This variant has been reported to segregate with autosomal recessive Alport syndrome in two families and has been identified in individuals with thin basement membrane disease with hematuria (PMID: 12631110, 9792860). ClinVar contains an entry for this variant (Variation ID: 17407). Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 19129241, 24052634, 11961012, 24854265). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne RCV001526639 SCV001737070 pathogenic Kidney damage criteria provided, single submitter clinical testing
OMIM RCV000018950 SCV000039237 pathogenic Alport syndrome, autosomal recessive 1998-11-01 no assertion criteria provided literature only
Gharavi Laboratory,Columbia University RCV000681673 SCV000809119 pathogenic not provided 2018-09-16 no assertion criteria provided research
Bioscientia Institut fuer Medizinische Diagnostik GmbH,Sonic Healthcare RCV000787008 SCV000925916 pathogenic Alport syndrome 3, autosomal dominant 2019-01-03 no assertion criteria provided clinical testing
Sydney Genome Diagnostics,Children's Hospital Westmead RCV001328062 SCV001449250 pathogenic Alport syndrome 2018-10-24 no assertion criteria provided clinical testing This patient is heterozygous for a known pathogenic variant, c.4139C>T p.(Arg1377*), in the COL4A4 gene. This variant (dbSNP: rs121912861) creates a premature stop codon p.(Arg1377*), and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be pathogenic, and has been previously reported in conjunction with a second pathogenic mutation in two patients with Alport syndrome in the literature (Boye et al 1998 Am. J. Hum. Genet. 63:1329-40).

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