Submissions for variant NM_000092.5(COL4A4):c.4129C>T (p.Arg1377Ter)

gnomAD frequency: 0.00001  dbSNP: rs121912861

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV001251501	SCV001427120	pathogenic	Benign familial hematuria	2018-06-28	criteria provided, single submitter	clinical testing	A heterozygous nonsense variant, NM_000092.4(COL4A4):c.4129C>T, has been identified in exon 44 of 48 of the COL4A4 gene. The variant is predicted to result in a premature stop codon at position 1377 of the protein, NP_000083.3(COL4A4):p.(Arg1377*). This variant is predicted to result in loss of protein function either through truncation (including loss of a quarter of the protein) or nonsense-mediated decay, which is a reported mechanism of pathogenicity for this gene. The variant is present in the gnomAD database at a frequency of 0.00081% (2 heterozygotes, 0 homozygote). The variant has previously been described as pathogenic in multiple patients with Alport syndrome (ClinVar, Boye, E., et al. (1998), Buzza, M., et al. (2001), Buzza, M., et al. (2003)) and has also been shown to segregate with haematuria in these families. In addition, other truncating variants upstream and downstream of this variant have been reported as pathogenic in individuals with Alport sydrome. Based on the information available at the time of curation, this variant has been classified as PATHOGENIC.
Invitae	RCV000681673	SCV001578221	pathogenic	not provided	2024-01-16	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Arg1377*) in the COL4A4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL4A4 are known to be pathogenic (PMID: 21196518, 24854265, 25307543). This variant is present in population databases (rs121912861, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with autosomal recessive Alport syndrome and/or thin basement membrane disease with hematuria (PMID: 9792860, 12631110). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 17407). For these reasons, this variant has been classified as Pathogenic.
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV001526639	SCV001737070	pathogenic	Kidney damage		criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000018950	SCV002060298	pathogenic	Autosomal recessive Alport syndrome	2021-11-16	criteria provided, single submitter	clinical testing	NM_000092.4(COL4A4):c.4129C>T(R1377*) is a nonsense variant classified as pathogenic in the context of COL4A4-related Alport syndrome. R1377* has been observed in cases with relevant disease (PMID: 9792860). Functional assessments of this variant are not available in the literature. R1377* has been observed in population frequency databases (gnomAD: ASJ 0.01%). In summary, NM_000092.4(COL4A4):c.4129C>T(R1377*) is a nonsense variant in a gene where loss of function is a known mechanism of disease and is predicted to disrupt protein function. Please note: this variant was assessed in the context of healthy population screening.
GeneDx	RCV000681673	SCV004023706	pathogenic	not provided	2023-02-03	criteria provided, single submitter	clinical testing	Identified in a patient with thin basement membrane disease in published literature (Buzza et al., 2003); variant reported to segregate with additional family members with hematuria but data is limited; Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25525159, 31589614, 33712733, 31576025, 30586318, 9792860, 32939031, 12631110)
PreventionGenetics, part of Exact Sciences	RCV003407346	SCV004108865	pathogenic	COL4A4-related condition	2022-12-20	criteria provided, single submitter	clinical testing	The COL4A4 c.4129C>T variant is predicted to result in premature protein termination (p.Arg1377*). This variant has been reported in the compound heterozygous or homozygous state in individuals with autosomal recessive Alport syndrome (Family AR18 in Boye et al 1998. PubMed ID: 9792860; Jayasinghe K et al 2020. PubMed ID: 32939031; Gillion V et al. 2018. PubMed ID: 29854973). This variant in the heterozygous state or compound heterozygous state has also been reported in individuals with hematuria (Buzza et al. 2003. PubMed ID: 12631110; Schrezenmeier et al. 2021. PubMed ID: 33712733; Zhang et al. 2020. PubMed ID: 31576025). This variant is reported in 0.0099% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-227886851-G-A). Nonsense variants in COL4A4 are expected to be pathogenic. This variant is interpreted as pathogenic.
OMIM	RCV000018950	SCV000039237	pathogenic	Autosomal recessive Alport syndrome	1998-11-01	no assertion criteria provided	literature only
Gharavi Laboratory, Columbia University	RCV000681673	SCV000809119	pathogenic	not provided	2018-09-16	no assertion criteria provided	research
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000787008	SCV000925916	pathogenic	Autosomal dominant Alport syndrome	2019-01-03	no assertion criteria provided	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328062	SCV001449250	pathogenic	Alport syndrome	2018-10-24	no assertion criteria provided	clinical testing	This patient is heterozygous for a known pathogenic variant, c.4139C>T p.(Arg1377*), in the COL4A4 gene. This variant (dbSNP: rs121912861) creates a premature stop codon p.(Arg1377*), and may result in a null allele due to nonsense-mediated mRNA decay. This variant is considered to be pathogenic, and has been previously reported in conjunction with a second pathogenic mutation in two patients with Alport syndrome in the literature (Boye et al 1998 Am. J. Hum. Genet. 63:1329-40).
Natera, Inc.	RCV001328062	SCV002078862	pathogenic	Alport syndrome	2020-02-22	no assertion criteria provided	clinical testing