ClinVar Miner

Submissions for variant NM_000092.4(COL4A4):c.4760C>G (p.Pro1587Arg) (rs190148408)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Athena Diagnostics Inc RCV000518567 SCV000612971 uncertain significance not specified 2016-11-02 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000518567 SCV000966417 likely benign not specified 2018-06-04 criteria provided, single submitter clinical testing p.Pro1587Arg in exon 47 of COL4A4: This variant is classified as likely benign, because although it has been reported in 3 individuals with features of Alport s yndrome (Chatterjee 2013, Mencarelli 2015, Sen 2017), it is present in 0.34% (43 0/126088) of European chromosomes by the Genome Aggregation Database (gnomAD, ht tp://; dbSNP rs190148408). This allele frequency is too high to cause Alport syndrome or hearing loss due to the COL4A4 gene. ACMG/AMP criteria applied: BS1.
GeneDx RCV000835693 SCV000977498 likely benign not provided 2018-04-27 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Invitae RCV000835693 SCV001024487 likely benign not provided 2020-12-05 criteria provided, single submitter clinical testing
Mendelics RCV000987042 SCV001136230 uncertain significance Alport syndrome 1, X-linked recessive 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001139982 SCV001300184 uncertain significance Alport syndrome 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000835693 SCV001552564 uncertain significance not provided no assertion criteria provided clinical testing The COL4A4 p.Pro1587Arg variant was identified in the literature however the frequency of this variant in an affected population was not provided. The variant was found in 1/11 families with Alport syndrome in the proband and two brothers all affected with haematuria and proteinuria as well as the father who was affected with end-stage renal disease (Mencarelli_2015_PMID: 25575550). This family also carried another variant in COL4A4 (c.1623+5G>T) and a variant in COL4A5 (p.Gly684Val), which the authors suggested may have led to a triallelic form of digenic inheritance of the renal phenotype observed in this family (Mencarelli_2015_PMID: 25575550). The p.P1587R variant was also found in a male proband, age 75, with hereditary nephritis who also had a variant in the COL4A3 gene (Chatterjee_2013_PMID: 24130771). The proband’s brother and sister had end stage renal disease related to presumed hereditary nephritis, however they were not tested for the variant (Chatterjee_2013_PMID: 24130771). The variant was also identified in dbSNP (ID: rs190148408), ClinVar (classified as a VUS by Athena Diagnostics), Cosmic (FATHMM prediction of neutral; score=0.42) and LOVD 3.0 (reported as likely pathogenic in 3 patients with Alport Syndrome, and as VUS in 6 patients with Alport Syndrome). The variant was identified in control databases in 575 of 279544 chromosomes (2 homozygous) at a frequency of 0.002057 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European (non-Finnish) in 438 of 127990 chromosomes (freq: 0.003422), Other in 16 of 7120 chromosomes (freq: 0.002247), South Asian in 57 of 30568 chromosomes (freq: 0.001865), Ashkenazi Jewish in 19 of 10348 chromosomes (freq: 0.001836), African in 14 of 24012 chromosomes (freq: 0.000583), Latino in 19 of 35320 chromosomes (freq: 0.000538) and European (Finnish) in 12 of 24740 chromosomes (freq: 0.000485); it was not observed in the East Asian populations. The p.Pro1587 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.

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