Submissions for variant NM_001845.6(COL4A1):c.2285T>C (p.Val762Ala)

gnomAD frequency: 0.00009  dbSNP: rs374930028

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV001111630	SCV001269199	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Illumina Laboratory Services, Illumina	RCV002249713	SCV001269717	likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Johns Hopkins Genomics, Johns Hopkins University	RCV001357253	SCV001762348	likely benign	not provided	2021-06-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001357253	SCV002451255	likely benign	not provided	2025-01-30	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001357253	SCV002497687	likely benign	not provided	2022-09-01	criteria provided, single submitter	clinical testing	COL4A1: BP4, BS2
Ambry Genetics	RCV004032166	SCV004929924	likely benign	Inborn genetic diseases	2022-10-26	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.
GeneDx	RCV001357253	SCV005390895	uncertain significance	not provided	2025-02-11	criteria provided, single submitter	clinical testing	Has not been previously published as pathogenic or benign to our knowledge; Occurs in the triple helical domain at the X position in the canonical Gly-X-Y repeat; although this variant may have an effect on normal protein folding and function, missense substitution at the X position is not a common mechanism of disease; In silico analysis indicates that this missense variant does not alter protein structure/function
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001357253	SCV001552669	uncertain significance	not provided		no assertion criteria provided	clinical testing	The COL4A1 p.Val762Ala variant was not identified in the literature nor was it identified in the ClinVar, Cosmic or MutDB databases. The variant was identified in dbSNP (ID: rs374930028) and LOVD 3.0. The variant was identified in control databases in 20 of 282834 chromosomes at a frequency of 0.000071 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following population: European (Non-Finnish) in 20 of 129168 chromosomes (freq: 0.000155); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, and South Asian populations. The p.Val762 residue is not conserved in mammals and five out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out 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.