ClinVar Miner

Submissions for variant NM_000091.5(COL4A3):c.4523A>G (p.Asn1508Ser) (rs200512461)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Illumina Clinical Services Laboratory,Illumina RCV000337893 SCV000428194 uncertain significance Alport syndrome 2018-01-13 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.
Counsyl RCV000673190 SCV000798365 uncertain significance Alport syndrome, autosomal recessive 2018-03-09 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000825316 SCV000966611 uncertain significance not specified 2018-05-21 criteria provided, single submitter clinical testing The p.Asn1508Ser variant in COL4A3 has been reported in 1 Italian individual wit h end stage renal disease (ESRD), hematuria and proteinuria, who was also hetero zygous for a variant in another gene (COL4A4). The p.Asn1508Ser variant in COL4A 3 did not segregate in a sibling with hematuria and proteinuria, while the COL4 A4 variant was detected in that sibling (Fallerini 2017). This variant has also been identified in (52/126600) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs200512461). Althoug h this variant has been seen in the general population, its frequency is not hig h enough to rule out a pathogenic role. Computational prediction tools and conse rvation analysis do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the p.Asn1508Ser variant is unc ertain. ACMG/AMP Criteria Applied: PM2_Supporting, BS4_Supporting.
Invitae RCV001247514 SCV001420941 uncertain significance not provided 2019-11-27 criteria provided, single submitter clinical testing This sequence change replaces asparagine with serine at codon 1508 of the COL4A3 protein (p.Asn1508Ser). The asparagine residue is moderately conserved and there is a small physicochemical difference between asparagine and serine. This variant is present in population databases (rs200512461, ExAC 0.03%). This variant has been observed in individual(s) with clinical features of Alport syndrome (PMID: 27859054). ClinVar contains an entry for this variant (Variation ID: 334786). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Knight Diagnostic Laboratories, Oregon Health and Sciences University RCV000337893 SCV001448955 uncertain significance Alport syndrome 2019-11-14 criteria provided, single submitter clinical testing
GeneDx RCV001247514 SCV001770997 uncertain significance not provided 2021-11-23 criteria provided, single submitter clinical testing Observed with a COL4A4 variant in a patient with Alport syndrome in the published literature, however, the COL4A3 variant did not segregate with a second affected individual in the family (Fallerini 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: 27859054)
Natera, Inc. RCV001276579 SCV001462978 uncertain significance Alport syndrome 3, autosomal dominant 2020-06-11 no assertion criteria provided clinical testing

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