Submissions for variant NM_000554.6(CRX):c.28C>G (p.His10Asp)

gnomAD frequency: 0.00060  dbSNP: rs139340178

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Illumina Laboratory Services, Illumina	RCV000280624	SCV000413915	likely benign	Cone-rod dystrophy 2	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	RCV000787830	SCV000413916	uncertain significance	Retinitis pigmentosa	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Illumina Laboratory Services, Illumina	RCV000401704	SCV000413917	uncertain significance	Leber congenital amaurosis 7	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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Invitae	RCV001087610	SCV001020861	likely benign	Leber congenital amaurosis 7; Cone-rod dystrophy 2	2024-01-25	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000878021	SCV001151966	uncertain significance	not provided	2019-04-01	criteria provided, single submitter	clinical testing
GeneDx	RCV000878021	SCV003805607	likely benign	not provided	2018-09-19	criteria provided, single submitter	clinical testing	See Variant Classification Assertion Criteria.
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000787830	SCV000926843	uncertain significance	Retinitis pigmentosa	2018-04-01	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000878021	SCV001551218	uncertain significance	not provided		no assertion criteria provided	clinical testing	The CRX p.His10Asp variant was identified in the literature in individuals with retinitis pigmentosa and bipolar disorder (Sohocki_2001_PMID:11139241; Maaser_2018_PMID_11139241; Jespersgaard_2019_PMID:30718709). The variant was identified in dbSNP (ID: rs139340178) and ClinVar (classified as likely benign by Illumina and Invitae, and as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen and Medical Genetics Laboratory, Kennedy Center,Juliane Marie Center, Rigshospitalet). The variant was identified in control databases in 133 of 282854 chromosomes at a frequency of 0.0004702 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: Latino in 41 of 35432 chromosomes (freq: 0.001157), Other in 4 of 7228 chromosomes (freq: 0.000553), European (non-Finnish) in 69 of 129186 chromosomes (freq: 0.000534), South Asian in 15 of 30616 chromosomes (freq: 0.00049), African in 3 of 24950 chromosomes (freq: 0.00012) and European (Finnish) in 1 of 25118 chromosomes (freq: 0.00004), but was not observed in the Ashkenazi Jewish or East Asian populations. The p.His10 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. 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. 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.