Submissions for variant NM_001845.6(COL4A1):c.1402C>T (p.Leu468Phe)

gnomAD frequency: 0.00004  dbSNP: rs757163211

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000486711	SCV000572342	uncertain significance	not provided	2016-12-07	criteria provided, single submitter	clinical testing	The L468F variant in the COL4A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The L468F variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The L468F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret L468F as a variant of uncertain significance.
Athena Diagnostics	RCV000486711	SCV001879777	uncertain significance	not provided	2024-09-20	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000486711	SCV002154140	uncertain significance	not provided	2024-11-11	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 468 of the COL4A1 protein (p.Leu468Phe). This variant is present in population databases (rs757163211, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with COL4A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 422781). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL4A1 protein function with a negative predictive value of 95%. 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	RCV002496874	SCV002776614	uncertain significance	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome; Brain small vessel disease 1 with or without ocular anomalies; Hemorrhage, intracerebral, susceptibility to; Retinal arterial tortuosity; Microangiopathy and leukoencephalopathy, pontine, autosomal dominant	2021-12-30	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002526639	SCV003689298	uncertain significance	Inborn genetic diseases	2020-10-07	criteria provided, single submitter	clinical testing	The c.1402C>T (p.L468F) alteration is located in exon 23 (coding exon 23) of the COL4A1 gene. This alteration results from a C to T substitution at nucleotide position 1402, causing the leucine (L) at amino acid position 468 to be replaced by a phenylalanine (F). Based on data from the Genome Aggregation Database (gnomAD) database, the COL4A1 c.1402C>T alteration was observed in <0.01% (9/251150) of total alleles studied, with a frequency of 0.02% (6/34590) in the Latino subpopulation. This amino acid position is not well conserved in available vertebrate species. The p.L468F alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
Revvity Omics, Revvity	RCV000486711	SCV003828150	uncertain significance	not provided	2022-09-13	criteria provided, single submitter	clinical testing