Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gharavi Laboratory, |
RCV000681779 | SCV000809242 | pathogenic | not provided | 2018-09-16 | criteria provided, single submitter | research | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000021453 | SCV002819763 | pathogenic | X-linked Alport syndrome | 2022-12-23 | criteria provided, single submitter | clinical testing | Variant summary: COL4A5 c.2917+1G>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Lv_2020). The variant was absent in 180606 control chromosomes. c.2917+1G>C has been reported in the literature as a hemizygous genotype in two patients affected with Alport Syndrome 1, X-Linked Recessive (Knebelman_1996, Groopman_2019) and as a heterozygous genotype in 2 females (proband and mother) with Hematuria, a related phenotype (Lv_2020). These data indicate that the variant is likely to be associated with disease. Two clinical diagnostic laboratories have submitted clinical-significance assessments to ClinVar after 2014 and classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. |
| Invitae | RCV000681779 | SCV004299693 | pathogenic | not provided | 2023-06-28 | criteria provided, single submitter | clinical testing | For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in multiple RNA products (PMID: 32659759). ClinVar contains an entry for this variant (Variation ID: 24574). This variant is also known as c.3119+1G>C. Disruption of this splice site has been observed in individuals with Alport syndrome (PMID: 8940267, 32659759). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 33 of the COL4A5 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 COL4A5 are known to be pathogenic (PMID: 9195222, 10752524, 14514738, 24854265, 26809805). |
| Institute of Clinical Laboratory Science, |
RCV000021453 | SCV001190327 | pathogenic | X-linked Alport syndrome | 2017-05-21 | no assertion criteria provided | in vitro | A heterozygous variant c.2767g > t (p.gly923cys) was found in exon 32 of COL4A5 gene in the proband, which is a new variant. Sanger sequencing confirmed that the mutation was co isolated from the disease in the family. In vitro minigene experiment showed that the mutation of c.2767g > t could cause 96 bases missing in exon 33 of COL4A5 gene |