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

gnomAD frequency: 0.00003  dbSNP: rs757328549

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics Inc	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