ClinVar Miner

Submissions for variant NM_000092.5(COL4A4):c.4708G>A (p.Glu1570Lys)

gnomAD frequency: 0.00003  dbSNP: rs757328549
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics RCV000991624 SCV001143241 uncertain significance not provided 2020-09-01 criteria provided, single submitter clinical testing
Illumina Laboratory Services, Illumina RCV001140737 SCV001301023 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.
GeneDx RCV000991624 SCV002043949 uncertain significance not provided 2021-06-22 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27535533, 30647093, 31408864)
Myriad Genetics, Inc. RCV000859980 SCV002060099 uncertain significance Autosomal recessive Alport syndrome 2021-11-10 criteria provided, single submitter clinical testing NM_000092.4(COL4A4):c.4708G>A(E1570K) is a missense variant classified as a variant of uncertain significance in the context of COL4A4-related Alport syndrome. E1570K has been observed in cases with relevant disease (PMID: 31408864, Sanchez_2018_(no PMID; abstract)). Functional assessments of this variant are not available in the literature. E1570K has been observed in population frequency databases (gnomAD: SAS 0.02%). In summary, there is insufficient evidence to classify NM_000092.4(COL4A4):c.4708G>A(E1570K) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening.
Fulgent Genetics, Fulgent Genetics RCV002477790 SCV002779900 uncertain significance Autosomal recessive Alport syndrome; Benign familial hematuria 2022-04-22 criteria provided, single submitter clinical testing
Invitae RCV000991624 SCV003439670 uncertain significance not provided 2021-10-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1570 of the COL4A4 protein (p.Glu1570Lys). This variant is present in population databases (rs757328549, gnomAD 0.02%). This missense change has been observed in individual(s) with COL4A4-related conditions (PMID: 30647093). ClinVar contains an entry for this variant (Variation ID: 634650). 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"). 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.
Division of Nephrology, Beth Israel Deaconess Medical Center RCV000859980 SCV000920872 likely pathogenic Autosomal recessive Alport syndrome no assertion criteria provided provider interpretation The c.4708G>A variant in COL4A4 was observed along with another COL4A4 variant, c.3861delinsCTC, in a female patient with clinical and renal biopsy findings consistent with Alport Syndrome. This patient was interpreted as being compound heterozygous for variants causing autosomal recessive Alport Syndrome. This patient had a relatively mild phenotype. This case manuscript is under revision for publication.
Natera, Inc. RCV001140737 SCV001459913 uncertain significance Alport syndrome 2020-09-16 no assertion criteria provided clinical testing

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