Submissions for variant NM_000092.5(COL4A4):c.2628_2654dup (p.Arg877_Gly885dup)

dbSNP: rs1553641597

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480791	SCV000572535	uncertain significance	not provided	2016-12-23	criteria provided, single submitter	clinical testing	The c.2628_2654dup27 variant in the COL4A4 gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2628_2654dup27 variant causes an in-frame duplication of nine amino acid residues within the triple helical region of the COL4A4 protein, beginning with Arginine 877 and ending with Glycine 885, denoted p.Arg877_Gly885dup. The c.2628_2654dup27 variant was not observed in approximately 5,900 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2628_2654dup27 as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000480791	SCV001483189	uncertain significance	not provided	2021-08-31	criteria provided, single submitter	clinical testing	This variant, c.2628_2654dup, results in the insertion of 9 amino acid(s) to the COL4A4 protein (p.Arg877_Gly885dup), but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with COL4A4-related conditions. ClinVar contains an entry for this variant (Variation ID: 422936). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Centro de Bioquimica y Genetica Clinica, Servicio Murciano de Salud	RCV002244953	SCV002515802	pathogenic	Autosomal dominant Alport syndrome	2022-05-19	criteria provided, single submitter	clinical testing	The p.(Arg877_Glu885dup) variant does not produce a frameshift; however, it results in a 9 amino acid increase in the length of the α4 chain of type IV collagen, in a non-repetitive "triple helix" region of the protein. This variant has been identified in heterozygous state in 7 families from our internal database of patients with symptoms of Alport syndrome or familial microhematuria, and was absent in the rest of our patients without kidney disease. Segregation studies in three of the affected families showed that this duplication co-segregated with the presence of kidney disease. The c.2628_2654dup variant meets the ACMG criteria: PM1, PM2, PM4, PP1 and PS4, and is classified as Pathogenic
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004787789	SCV005398724	pathogenic	Alport syndrome	2022-02-02	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 - 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 inheritance (OMIM, PMIDs: 16467446, 17942953). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2, v3) <0.001 for a dominant condition (1 heterozygote, 0 homozygotes). (SP) 0601 - Variant is located in the well-established functional G-X-Y triple helical region (Uniprot). (SP) 0705 - No comparable inframe duplication variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported as a VUS (ClinVar), and as likely pathogenic and observed in a homozygous individual of unclear phenotype (LOVD). However, more recently it has been reported in at least four unrelated families with autosomal dominant Alport syndrome, and classified as likely pathogenic (PMID: 33838161). (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
Fulgent Genetics, Fulgent Genetics	RCV005018814	SCV005649070	likely pathogenic	Autosomal recessive Alport syndrome; Hematuria, benign familial, 1	2024-05-15	criteria provided, single submitter	clinical testing
Institute of Human Genetics, Cologne University	RCV000495560	SCV000583562	uncertain significance	Autosomal recessive Alport syndrome		no assertion criteria provided	clinical testing