Submissions for variant NM_000092.5(COL4A4):c.2161C>T (p.Pro721Ser)

gnomAD frequency: 0.00012  dbSNP: rs200759521

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Institute of Human Genetics, University of Leipzig Medical Center	RCV001262385	SCV001440232	uncertain significance	Autosomal recessive Alport syndrome	2019-01-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001586098	SCV001813803	uncertain significance	not provided	2023-06-12	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Occurs in the triple helical domain at the Y position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the Y position is not a common mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge
Labcorp Genetics (formerly Invitae), Labcorp	RCV001586098	SCV002393851	likely benign	not provided	2024-01-12	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001830063	SCV005399943	uncertain significance	Alport syndrome	2021-05-06	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Loss of function is a known mechanism of disease for this gene and is associated with COL4A4-related nephropathy. Dominant negative is a suspected mechanism of disease for this gene as it is a structural protein (PMIDs: 12028435, 24046192). (I) 0108 - This gene is associated with both recessive and dominant disease. Alport syndrome typically has biallelic inheritance, although rare cases of monoallelic inheritance have been reported (PMID: 28704582). TBMN and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inhertitance (OMIM, PMIDs: 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to serine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 23 heterozygotes, 0 homozygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated triple helical region, and affects the Y residue of the Gly-X-Y repeat (UniProt, NCBI conserved domain). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0809 - Previous evidence of pathogenicity for this variant is inconclusive. This variant has been classified once as a variant of uncertain significance by a clinical diagnostic laboratory and has not been reported elsewhere in the literature (ClinVar). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Natera, Inc.	RCV001830063	SCV002078903	uncertain significance	Alport syndrome	2020-02-10	no assertion criteria provided	clinical testing