Submissions for variant NM_001384910.1(GUCA1A):c.149C>T (p.Pro50Leu)

gnomAD frequency: 0.00130  dbSNP: rs104893968

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000444625	SCV000513203	uncertain significance	not provided	2017-01-03	criteria provided, single submitter	clinical testing	The P50L variant in the GUCA1A gene has been reported previously in three members of a family with variable ocular abnormalities, ranging from minimal macular involvement to moderately severe cone-rod dystrophy (Downes et al., 2001). The P50L variant was also identified in a patient with cone and cone-rod dystrophy, however, informative familial segregation data was not included to confirm if this variant occurred de novo or was inherited in this individual (Boulanger-Scemama et al., 2015). The NHLBI ESP Exome Sequencing Project reports P50L was observed in 0.12% (10/8600) alleles from individuals of European American ancestry, indicating it may be a rare (benign) variant in this population. The P50L variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. One in vitro functional study concluded that this variant results in impaired calcium binding, however, enzyme assays showed similar results for the P50L variant compared to wild type enzyme, and it is unclear how this variant impacts the protein function (Sokal et al., 2000). In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We now interpret P50L as a variant of uncertain significance.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000444625	SCV001033698	likely benign	not provided	2024-12-07	criteria provided, single submitter	clinical testing
OMIM	RCV000009722	SCV000029941	pathogenic	Cone dystrophy 3	2001-01-01	no assertion criteria provided	literature only
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787609	SCV000926593	pathogenic	Macular dystrophy	2018-04-01	no assertion criteria provided	research
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787610	SCV000926594	pathogenic	Usher syndrome	2018-04-01	no assertion criteria provided	research
Clinical Genetics, Academic Medical Center	RCV000444625	SCV001920532	likely benign	not provided		no assertion criteria provided	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000444625	SCV001965175	likely benign	not provided		no assertion criteria provided	clinical testing