Submissions for variant NM_000091.5(COL4A3):c.3312AAGTCCTGG[1] (p.1105SPG[1])

dbSNP: rs756539994

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
CeGaT Center for Human Genetics Tuebingen	RCV001092433	SCV001248946	pathogenic	not provided	2017-05-01	criteria provided, single submitter	clinical testing
Laboratory for Molecular Genetics, Institute of Pathology, Faculty of Medicine, University of Ljubljana	RCV000669324	SCV001443771	pathogenic	Autosomal recessive Alport syndrome	2020-11-18	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000669324	SCV002060373	uncertain significance	Autosomal recessive Alport syndrome	2021-11-10	criteria provided, single submitter	clinical testing	NM_000091.4(COL4A3):c.3321_3329del9(S1108_G1110del) is an in-frame deletion variant classified as a variant of uncertain significance in the context of COL4A3-related Alport syndrome. S1108_G1110del has been observed in a case with relevant disease (PMID: 33233744). Functional assessments of this variant are not available in the literature. S1108_G1110del has been observed in population frequency databases (gnomAD: AMR 0.01%). In summary, there is insufficient evidence to classify NM_000091.4(COL4A3):c.3321_3329del9(S1108_G1110del) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001844215	SCV002104169	uncertain significance	not specified	2023-12-07	criteria provided, single submitter	clinical testing	Variant summary: COL4A3 c.3321_3329delAAGTCCTGG (p.Ser1108_Gly1110del) results in an in-frame deletion that is predicted to remove three amino acids from the encoded protein. The variant allele was found at a frequency of 4.4e-05 in 249378 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in COL4A3 causing Alport Syndrome, Autosomal Recessive (4.4e-05 vs 0.0019), allowing no conclusion about variant significance. c.3321_3329delAAGTCCTGG has been reported in the literature as a non-informative genotype in individuals affected with microhematuria, proteinuria and other renal manifestations (example, Longo_2002, Frasca_2005, Zupan_2020). These report(s) do not provide unequivocal conclusions about association of the variant with Alport Syndrome, Autosomal Recessive. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 15618242, 36013122, 36292665, 12028435, 33233744). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (pathogenic/likely pathogenic, n=5; VUS, n=2). Based on the evidence outlined above, the variant was classified as uncertain significance.
Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	RCV001029825	SCV002764994	likely pathogenic	Autosomal dominant Alport syndrome	2022-07-29	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001092433	SCV003525006	uncertain significance	not provided	2024-04-13	criteria provided, single submitter	clinical testing	This variant, c.3321_3329del, results in the deletion of 3 amino acid(s) of the COL4A3 protein (p.Ser1108_Gly1110del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs756539994, gnomAD 0.01%). This variant has been observed in individuals with clinical features of Alport syndrome (PMID: 12028435; Invitae). This variant is also known as c.3321del9. ClinVar contains an entry for this variant (Variation ID: 553803). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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.
PreventionGenetics, part of Exact Sciences	RCV003392510	SCV004120052	likely pathogenic	COL4A3-related disorder	2023-10-05	criteria provided, single submitter	clinical testing	The COL4A3 c.3321_3329del9 variant is predicted to result in an in-frame deletion (p.Ser1108_Gly1110del). This variant was reported in a female patient with microhematuria and proteinuria and other COL4A variants were not reported (Longo et al 2002. PubMed ID: 12028435).The c.3321_3329del9 variant was also reported with either COL4A4 or COL4A5 Gly substitution variants in three family members of a large family with proposed digenic inheritance for COL4A-related disorders (reported as c.3307_3315del in Zupan A et al 2020. PubMed ID: 33233744). At PreventionGenetics, we have observed the c.3321_3329del9 variant in the presence of a second COL4A3 variant in two patients with renal disorders (internal data). This variant is reported in 0.011% of alleles in individuals of Latino descent in gnomAD, indicating this variant may not be a primary cause of disease in the heterozygous state (http://gnomad.broadinstitute.org/variant/2-228158002-CCCTGGAAGT-C). This variant is interpreted as likely pathogenic for autosomal recessive COL4A3-related disorders.
Laboratory of Medical Genetics, National & Kapodistrian University of Athens	RCV004568524	SCV005051727	likely pathogenic	Alport syndrome 3b, autosomal recessive	2024-02-01	criteria provided, single submitter	curation
GeneDx	RCV001092433	SCV005333740	likely pathogenic	not provided	2024-03-28	criteria provided, single submitter	clinical testing	In-frame deletion of 3 amino acids within the triple helical domain; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 15618242, 36013122, 36292665, 33233744, 12028435)
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV004788091	SCV005398466	likely pathogenic	Alport syndrome	2024-10-08	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely 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 (Alport syndrome 2 MIM#203780) and dominant disease (Alport syndrome 3 MIM#104200 and benign familial hematuria MIM#141200) (OMIM). (I) 0216 - In-frame deletion in a non-repetitive region that has low conservation. (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 (v2: 12 heterozygotes, 0 homozygotes). (SP) 0601 - Variant is located in the well-established functional triple helical domain (DECIPHER). However, this in-frame deletion restores a G-X-Y repeat. (SP) 0705 - No comparable in-frame deletion or missense variants have previous evidence for pathogenicity. (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been observed in three heterozygote individuals, one with Alport syndrome (PMID: 12028435), one with bilateral hearing loss and congenital hypothyroidism (PMID: 34178707) and one with haematuria and proteinuria (VCGS internal database). It has also been classified as likely pathogenic or pathogenic by diagnostic laboratories in ClinVar, as well as VUS classifications. (SP) 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
Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	RCV004568524	SCV005438327	uncertain significance	Alport syndrome 3b, autosomal recessive	2024-12-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV004972844	SCV005568991	uncertain significance	Inborn genetic diseases	2024-06-28	criteria provided, single submitter	clinical testing	The c.3321_3329delAAGTCCTGG (p.S1108_G1110del) alteration is located in exon 38 (coding exon 38) of the COL4A3 gene. This alteration consists of an in-frame deletion of 9 nucleotides between nucleotide positions c.3321 and c.3329, resulting in the deletion of 3 residues. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Fulgent Genetics, Fulgent Genetics	RCV005027802	SCV005656050	likely pathogenic	Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive	2024-03-23	criteria provided, single submitter	clinical testing
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV001029825	SCV001192608	likely pathogenic	Autosomal dominant Alport syndrome	2019-08-07	no assertion criteria provided	clinical testing