Submissions for variant NM_000091.5(COL4A3):c.4664C>T (p.Ala1555Val)

dbSNP: rs369575989

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001348296	SCV001542594	pathogenic	not provided	2024-04-25	criteria provided, single submitter	clinical testing	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1555 of the COL4A3 protein (p.Ala1555Val). This variant is present in population databases (rs369575989, gnomAD 0.04%). This missense change has been observed in individual(s) with clinical features of Alport syndrome (PMID: 27281700, 28780565, 29742505, 30076350, 30883042, 31328266, 35386907). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1044092). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL4A3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic.
GeneDx	RCV001348296	SCV002757483	uncertain significance	not provided	2022-05-27	criteria provided, single submitter	clinical testing	Reported with a second COL4A3 variant or a COL4A4 variant (phase unknown) in unrelated patients with COL4A3-related features in published literature (Sen et al., 2017; Li et al., 2018); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 28780565, 30883042, 30076350, 29742505, Liu2019[paper], 30881523, 35386907)
Fulgent Genetics, Fulgent Genetics	RCV005023072	SCV005656151	uncertain significance	Autosomal dominant Alport syndrome; Hematuria, benign familial, 2; Alport syndrome 3b, autosomal recessive	2024-06-19	criteria provided, single submitter	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001348296	SCV001957717	uncertain significance	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV001348296	SCV001966153	uncertain significance	not provided		no assertion criteria provided	clinical testing
Natera, Inc.	RCV001831140	SCV002076438	uncertain significance	Alport syndrome	2020-01-20	no assertion criteria provided	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004743417	SCV005363879	uncertain significance	COL4A3-related disorder	2024-04-15	no assertion criteria provided	clinical testing	The COL4A3 c.4664C>T variant is predicted to result in the amino acid substitution p.Ala1555Val. This variant has been reported, with another variant(s) in COL4A3 in some cases, in individuals with COL4A3-related disorders (Table S3, Sen et al. 2017. PubMed ID: 28780565; Table S3, Rao et al. 2019. PubMed ID: 31328266; Table S2, Kaymiyoshi et al. 2016. PubMed IDF: 27281700; Li et al. 2018. PubMed ID: 29742505; Deng et al. 2022. PubMed ID: 35386907). Of note, in a study of a large family with benign familial hematuria, the segregation analysis demonstrated this variant was inherited from the unaffected father; and the proband also has a heterozygous likely pathogenic variant c.3418+1G>T in COL4A3, which is likely the primary cause of benign familial hematuria (Li et al. 2018. PubMed ID: 29742505). The c.4664C>T (p.Ala1555Val) variant is reported in 0.041% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.