ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.4470del (p.Tyr1491fs)

dbSNP: rs1963392922
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV001233078 SCV001405658 pathogenic not provided 2023-10-19 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Tyr1491Ilefs*61) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Alport syndrome (PMID: 28844315). ClinVar contains an entry for this variant (Variation ID: 959686). For these reasons, this variant has been classified as Pathogenic.
3billion RCV001809999 SCV002058923 pathogenic Autosomal recessive Alport syndrome 2022-01-03 criteria provided, single submitter clinical testing Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported to be associated with COL4A4 related disorder (ClinVar ID: VCV000959686, PMID:28844315, 3billion dataset). The variant was co-segregated with Alport syndrome 2 in multiple affected family members (PP1_P, 3billlion dataset). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Sydney Genome Diagnostics, Children's Hospital Westmead RCV001328061 SCV001449249 pathogenic Alport syndrome 2018-10-24 no assertion criteria provided clinical testing This patient is heterozygous for the c.4470del variant in the COL4A4 gene. This frameshifting variant is predicted to create a premature stop codon 60 amino acid positions downstream p.(Trp1491Ilefs*61), and may result in a null allele due to nonsense-mediated mRNA decay. To our knowledge, this variant has not been previously reported. However, other nonsense variants downstream of this amino acid has been previously reported in the literature in Alports patients (Boye et al 1998 Am. J. Hum. Genet. 63:1329-40). This variant is considered to be pathogenic.

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