Total submissions: 9
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Counsyl | RCV000505603 | SCV000793901 | likely pathogenic | Autosomal recessive Alport syndrome | 2017-09-12 | criteria provided, single submitter | clinical testing | |
| Fulgent Genetics, |
RCV001535988 | SCV001752659 | likely pathogenic | Autosomal recessive Alport syndrome; Benign familial hematuria | 2021-06-30 | criteria provided, single submitter | clinical testing | |
| Centogene AG - |
RCV000505603 | SCV002098117 | likely pathogenic | Autosomal recessive Alport syndrome | 2022-02-21 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001857239 | SCV002205053 | pathogenic | not provided | 2023-10-25 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 9 of the COL4A4 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and 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). Disruption of this splice site has been observed in individual(s) with clinical features of autosomal recessive Alport syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 438704). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. |
| MGZ Medical Genetics Center | RCV002289691 | SCV002579182 | pathogenic | Benign familial hematuria | 2022-04-20 | criteria provided, single submitter | clinical testing | |
| Eurofins- |
RCV000505603 | SCV003935045 | pathogenic | Autosomal recessive Alport syndrome | 2022-10-14 | criteria provided, single submitter | clinical testing | |
| Institute Of Human Genetics Munich, |
RCV002289691 | SCV004045915 | pathogenic | Benign familial hematuria | 2022-10-18 | criteria provided, single submitter | clinical testing | |
| ARUP Laboratories, |
RCV001857239 | SCV004563657 | likely pathogenic | not provided | 2023-05-10 | criteria provided, single submitter | clinical testing | The COL4A4 c.594+1G>A variant (rs1553690565), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 438704). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 9, which is likely to negatively impact gene function. Different variants in this same intron (c.594+5G>A and c.595-1G>A) have been identified in patients with symptoms of Alport spectrum disorder (Horinouchi 2020 and Gao 2023). Based on available information, the c.594+1G>A variant is considered to be likely pathogenic. References: Gao Y et al. Identification of COL4A4 variants in Chinese patients with familial hematuria. Front Genet. 2023 Jan 9;13:1064491 PMID: 36699462 Horinouchi T et al. Heterozygous Urinary Abnormality-Causing Variants of COL4A3 and COL4A4 Affect Severity of Autosomal Recessive Alport Syndrome. Kidney360. 2020 Jul 16;1(9):936-942. PMID: 35369551 |
| Bioscientia Institut fuer Medizinische Diagnostik Gmb |
RCV000505603 | SCV000599862 | pathogenic | Autosomal recessive Alport syndrome | 2017-04-20 | no assertion criteria provided | clinical testing |