ClinVar Miner

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

dbSNP: rs756539994
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Total submissions: 8
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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
Invitae RCV001092433 SCV003525006 uncertain significance not provided 2022-10-24 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.
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

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