Submissions for variant NM_000092.5(COL4A4):c.4421C>T (p.Thr1474Met)

gnomAD frequency: 0.00005  dbSNP: rs201615111

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000407621	SCV000428069	uncertain significance	Alport syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
GeneDx	RCV001660696	SCV001875206	uncertain significance	not provided	2023-03-29	criteria provided, single submitter	clinical testing	Reported as heterozygous in patients with focal segmental glomerulosclerosis in published literature who also harbored variants in other collagen genes (Wang et al., 2017); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30968591, 32703181, 32332277, 28476686, 31328266)
3billion, Medical Genetics	RCV002283476	SCV002573136	pathogenic	Autosomal recessive Alport syndrome	2024-07-30	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v4.0.0 dataset (total allele frequency: 0.006%). in silico tool predictions suggest damaging effect of the variant on gene or gene product [3Cnet: 0.67 (damaging >=0.6)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL4A4-related disorder (PMID: 28476686). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least 4 similarly affected unrelated individuals (PMID: 28476686 , 30968591 , 32332277 , 32703181). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline.
Genome Diagnostics Laboratory, The Hospital for Sick Children	RCV002294291	SCV002587173	uncertain significance	Kidney disorder	2019-08-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002504132	SCV002816780	uncertain significance	Autosomal recessive Alport syndrome; Benign familial hematuria	2022-04-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001660696	SCV003522201	benign	not provided	2024-12-21	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000407621	SCV005399640	uncertain significance	Alport syndrome	2023-07-17	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 Alport syndrome. 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). Thin basement membrane nephropathy (TBMN) and focal segmental glomerulosclerosis (FSGS) are associated with autosomal dominant inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0200 - Variant is predicted to result in a missense amino acid change from threonine to methionine. (I) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2+v3) <0.01 (47 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 C4 domain (DECIPHER). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been classified as a VUS by multiple clinical laboratories in ClinVar and more recently as pathogenic by a single submitter. This variant has been observed in compound heterozygous state in three individuals with Alport syndrome in the literature (PMIDs: 32332277, 32703181, 30968591). This variant has also been observed as a single heterozygous variant in another three individuals with Alport syndrome or steroid-resistant nephrotic syndrome, two of whom had other variants more likely to be the cause of their conditions (PMIDs: 32332277, 28476686, 30968591). (SP) 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.	RCV000407621	SCV002078861	uncertain significance	Alport syndrome	2020-01-16	no assertion criteria provided	clinical testing