Submissions for variant NM_001845.6(COL4A1):c.1837C>G (p.Pro613Ala)

gnomAD frequency: 0.00001  dbSNP: rs1432737813

Total submissions: 2

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	RCV002273042	SCV002557601	uncertain significance	Brain small vessel disease 1 with or without ocular anomalies	2022-02-02	criteria provided, single submitter	clinical testing	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0103 - Dominant negative and loss of function are known mechanisms of disease in this gene and are associated with COL4A1-related disorders. Missense variants affecting the glycine of the triple helix of collagen genes typically exert a dominant-negative effect however, functional studies proving this for COL4A1 is currently lacking (PMID: 16159887). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0112 - The condition associated with this gene has incomplete penetrance (PMID: 21625620, 30413629). (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to alanine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD <0.001 for a dominant condition (v2: 2 heterozygotes, 0 homozygotes). (SP) 0309 - Multiple alternative amino acid change at the same position has been observed in gnomAD (highest allele count v2: 6 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated triple helical region. Specifically, it is the X of the GXY repeat (Uniprot, UCSC). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign
PreventionGenetics, part of Exact Sciences	RCV004534028	SCV004113774	uncertain significance	COL4A1-related disorder	2023-01-24	criteria provided, single submitter	clinical testing	The COL4A1 c.1837C>G variant is predicted to result in the amino acid substitution p.Pro613Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.011% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-110838792-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.