Submissions for variant NM_001845.6(COL4A1):c.1588C>T (p.Pro530Ser)

gnomAD frequency: 0.00031  dbSNP: rs145172612

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000176542	SCV000228217	uncertain significance	not provided	2015-01-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000264390	SCV000382478	uncertain significance	Porencephalic cyst	2016-06-14	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000323259	SCV000382479	benign	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Illumina Laboratory Services, Illumina	RCV002247585	SCV000382480	benign	Brain small vessel disease 1 with or without ocular anomalies	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.
Fulgent Genetics, Fulgent Genetics	RCV000763877	SCV000894812	uncertain significance	Autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome; Brain small vessel disease 1 with or without ocular anomalies; Schizencephaly; Hemorrhage, intracerebral, susceptibility to; Retinal arterial tortuosity	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000176542	SCV001106714	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000176542	SCV001335005	likely benign	not provided	2024-06-01	criteria provided, single submitter	clinical testing	COL4A1: BS1
Ambry Genetics	RCV004020096	SCV004929922	likely benign	Inborn genetic diseases	2021-12-28	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000176542	SCV001550017	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL4A1 p.Pro530Ser variant was not identified in the literature nor was it identified in Cosmic. The variant was identified in dbSNP (ID: rs145172612), ClinVar (classified as a VUS by EGL Genetics, Illumina Clinical Services and Fulgent Genetics) and LOVD 3.0 (classified as a VUS). The variant was also identified in control databases in 107 of 282602 chromosomes (1 homozygous) at a frequency of 0.000379 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: European (non-Finnish) in 94 of 128944 chromosomes (freq: 0.000729), Other in 5 of 7212 chromosomes (freq: 0.000693), Latino in 6 of 35428 chromosomes (freq: 0.000169), African in 1 of 24958 chromosomes (freq: 0.00004) and South Asian in 1 of 30616 chromosomes (freq: 0.000033), while the variant was not observed in the Ashkenazi Jewish, East Asian and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Pro530 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume 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.
PreventionGenetics, part of Exact Sciences	RCV004537407	SCV004115010	uncertain significance	COL4A1-related disorder	2024-01-05	no assertion criteria provided	clinical testing	The COL4A1 c.1588C>T variant is predicted to result in the amino acid substitution p.Pro530Ser. This variant was reported in members from one family who are affected with Marfan syndrome and was classified as variant of uncertain significance (Aubart et al. 2018. PubMed ID: 30087447) and has been reported in a patient with a renal ciliopathy syndrome (Al Alawi I et al 2021. PubMed ID: 34354814). This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD including one homozygous individual. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.