Submissions for variant NM_000091.5(COL4A3):c.663_664del (p.Arg221fs)

dbSNP: rs1469479748

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Counsyl	RCV000668884	SCV000793558	likely pathogenic	Autosomal recessive Alport syndrome	2017-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000668884	SCV001361061	pathogenic	Autosomal recessive Alport syndrome	2022-02-16	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.663_664delAG (p.Arg221SerfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 1.6e-05 in 249216 control chromosomes. c.663_664delAG has been reported in the literature in at least one individual affected with Alport Syndrome, Autosomal Recessive (Storey_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Baylor Genetics	RCV001330982	SCV001522861	pathogenic	Autosomal dominant Alport syndrome	2019-01-18	criteria provided, single submitter	clinical testing	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868].
Labcorp Genetics (formerly Invitae), Labcorp	RCV001384278	SCV001583718	pathogenic	not provided	2025-01-01	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg221Serfs*5) in the COL4A3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A3 are known to be pathogenic (PMID: 8956999, 24854265, 26809805, 27281700). This variant is present in population databases (no rsID available, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Alport syndrome (PMID: 24052634). 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: 553434). For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001384278	SCV005324969	likely pathogenic	not provided	2024-01-24	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Reported with a second variant (phase unknown) in a patient with renal biopsy suggestive of Alport syndrome in published literature (PMID: 24052634); This variant is associated with the following publications: (PMID: 24052634)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788088	SCV005399699	pathogenic	Alport syndrome	2024-10-09	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with Alport syndrome, MONDO:0018965, COL4A3-related. Glycine changes that are part of a G-X-Y repeat in the triple helix of a collagen domain are known to have a dominant negative effect (PMID: 12028435). (I) 0108 - This gene is associated with both recessive and dominant disease, Alport syndrome 3B (MIM#620536) and Alport syndrome 3A (MIM#104200), respectively (OMIM). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 (4 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity. Many NMD-predicted variants have been reported as pathogenic (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported three times as pathogenic and once as likely pathogenic (ClinVar) and in an at least one compound heterozygous individual with autosomal recessive Alport syndrome (PMID:24052634). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign