Submissions for variant NM_033380.3(COL4A5):c.5048G>A (p.Arg1683Gln)

gnomAD frequency: 0.00002  dbSNP: rs104886308

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Athena Diagnostics	RCV000518046	SCV000612999	likely pathogenic	not provided	2018-12-11	criteria provided, single submitter	clinical testing	Found in at least one symptomatic patient. Predicted to have a damaging effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Damaging to protein function(s) relevant to disease mechanism.
Gharavi Laboratory, Columbia University	RCV000518046	SCV000809274	pathogenic	not provided	2018-09-16	criteria provided, single submitter	research
Labcorp Genetics (formerly Invitae), Labcorp	RCV000518046	SCV000961772	pathogenic	not provided	2023-11-24	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1677 of the COL4A5 protein (p.Arg1677Gln). This variant is present in population databases (rs104886308, gnomAD 0.04%). This missense change has been observed in individuals with adult-onset Alport syndrome (PMID: 9150741, 19919694, 20378821). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 10467). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL4A5 protein function. Experimental studies have shown that this missense change affects COL4A5 function (PMID: 18083113). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV000011213	SCV001439915	pathogenic	X-linked Alport syndrome	2019-01-01	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV000011213	SCV001752777	pathogenic	X-linked Alport syndrome	2022-02-06	criteria provided, single submitter	clinical testing
GeneDx	RCV000518046	SCV001796427	pathogenic	not provided	2024-11-05	criteria provided, single submitter	clinical testing	Published functional studies demonstrate p.(R1683Q) results in a loss of formation of the type IV collagen heterotrimers (PMID: 18083113); 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: 29144512, 30586318, 31027891, 37895203, 37547535, 29526710, 29204651, 9150741, 20378821, 19919694, 35643372, 18083113)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000011213	SCV002103517	pathogenic	X-linked Alport syndrome	2022-02-18	criteria provided, single submitter	clinical testing	Variant summary: COL4A5 c.5030G>A (p.Arg1677Gln) results in a conservative amino acid change located in the Collagen IV, non-collagenous domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.2e-05 in 183310 control chromosomes. c.5030G>A has been reported in the literature in multiple individuals affected with Alport Syndrome 1, X-Linked Recessive or Nephrosclerosis/deafness (e.g. Bekheirnia_2010, Ottlewski_2019). These data indicate that the variant is very likely to be associated with disease. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
MGZ Medical Genetics Center	RCV000011213	SCV002580335	likely pathogenic	X-linked Alport syndrome	2021-10-20	criteria provided, single submitter	clinical testing
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV000011213	SCV002767563	pathogenic	X-linked Alport syndrome	2022-09-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with X-linked Alport syndrome 1 (MIM#301050). Dominant negative is caused mostly glycine substitutions that affect the conformation of the protein, and loss of function can be caused by either protein truncating or missense variants (PMID: 24046192, PMID: 12028435). (I) 0110 - This gene is known to be associated with X-linked dominant disease. Males are typically more severely affected than females (PMID: 19965530). (I) 0115 - Variants in this gene are known to have variable expressivity. There is intrafamilial variability among affected carrier females, possibly due to variable X-inactivation (PMID: 14514738). (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0253 - Variant is hemizygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (4 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools and highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the C-terminal tandem repeated domain in type 4 collagen (NCBI conserved domain). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Arg1677Pro) and p.(Arg1677Leu) comparable variants have each been reported in an individual with Alport Syndrome, respectively (PMIDs: 11223851; 21505094). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant is an Ashkenazi Jewish founder mutation and has been classified as pathogenic in ClinVar (PMIDs: 9150741; 27627812). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. HEK293T cells carrying the p.(Arg1683Gln) mutant construct demonstrated impaired trimer formation ability with alpha-3 and alpha-4 collagen chains compared with the wild type construct (PMID: 29526710). (SP) 1102 - Strong phenotype match. (SP) 1208 - Inheritance information for this variant is not currently available. (I) Legend: (P) - Pathogenic, (N) - Neutral, (B) - Benign
Mayo Clinic Laboratories, Mayo Clinic	RCV000518046	SCV005413438	pathogenic	not provided	2023-11-03	criteria provided, single submitter	clinical testing	PP1_strong, PP3, PS4
OMIM	RCV000011213	SCV000031440	pathogenic	X-linked Alport syndrome	2003-06-01	no assertion criteria provided	literature only
GeneReviews	RCV000011213	SCV000057826	not provided	X-linked Alport syndrome		no assertion provided	literature only
Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	RCV000011213	SCV000925849	pathogenic	X-linked Alport syndrome	2019-02-13	no assertion criteria provided	clinical testing
Sydney Genome Diagnostics, Children's Hospital Westmead	RCV001328066	SCV001449288	pathogenic	Hematuria	2018-05-30	no assertion criteria provided	clinical testing	This patient is heterozygous for a known pathogenic variant, c.5030G>A (p.Arg1677Gln), in the COL4A5 gene. This variant (dbSNP: rs104886308), located in the C terminal domain of COL4A5, has been previously reported in numerous patients with adult-onset X-linked Alport syndrome in the literature (Barker et al 1997 Hum Genet 99:681-684; Pont-Kingdon et al 2009 BMC Nephrol 10:38; Bekheirnia et al 2010 J Am Soc Nephrol 21:876-883).
PreventionGenetics, part of Exact Sciences	RCV003934823	SCV004750581	pathogenic	COL4A5-related disorder	2024-02-09	no assertion criteria provided	clinical testing	The COL4A5 c.5030G>A variant is predicted to result in the amino acid substitution p.Arg1677Gln. This variant was reported in three independent Ashkenazi-American families with features of COL4A5-related disorders (Barker et al. 1997. PubMed ID: 9150741; Pont-Kingdon et al. 2009. PubMed ID: 19919694). This variant was also reported in a 57 year old female patient with mild chronic kidney disease (Table 2 in Lata et al. 2017. PubMed ID: 29204651) and in a male patient with nephrosclerosis and deafness and his mother with deafness (Ottlewski et al. 2019. PubMed ID: 31027891). This variant is reported in 0.040% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic.