Submissions for variant NM_000091.5(COL4A3):c.1927G>A (p.Gly643Ser)

gnomAD frequency: 0.00001  dbSNP: rs778034451

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000348330	SCV000428168	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.
Molecular Diagnostics Laboratory, M Health Fairview: University of Minnesota	RCV000761268	SCV000891226	likely pathogenic	Autosomal recessive Alport syndrome	2018-01-23	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000681803	SCV003522562	uncertain significance	not provided	2022-04-06	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 643 of the COL4A3 protein (p.Gly643Ser). This variant is present in population databases (rs778034451, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with COL4A3-related conditions. ClinVar contains an entry for this variant (Variation ID: 334764). 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: "Tolerated"; 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 disrupt the consensus splice site. 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.
Fulgent Genetics, Fulgent Genetics	RCV005027430	SCV005649024	pathogenic	Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive	2024-02-17	criteria provided, single submitter	clinical testing
3billion	RCV000761268	SCV005904572	uncertain significance	Autosomal recessive Alport syndrome	2023-06-05	criteria provided, single submitter	clinical testing	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.68; 3Cnet: 0.95). Same nucleotide change resulting in same amino acid change has been previously reported to be associated with COL4A3 related disorder (ClinVar ID: VCV000334764 /PMID: 30586318). However, the evidence of pathogenicity is insufficient at this time. Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline.
Gharavi Laboratory, Columbia University	RCV000681803	SCV000809272	likely pathogenic	not provided	2018-09-16	no assertion criteria provided	research