Submissions for variant NM_205861.3(DHDDS):c.908C>T (p.Ser303Leu)

gnomAD frequency: 0.00024  dbSNP: rs141852437

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000904699	SCV001049234	benign	Retinitis pigmentosa 59	2025-01-15	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001099449	SCV001255904	uncertain significance	Retinitis pigmentosa	2018-01-13	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001532941	SCV001748753	benign	not specified	2021-06-19	criteria provided, single submitter	clinical testing	Variant summary: DHDDS c.911C>T (p.Ser304Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00048 in 250986 control chromosomes, predominantly at a frequency of 0.01033 within the Ashkenazi Jewish subpopulation in the gnomAD database. This frequency is significantly higher than expected for a pathogenic variant in DHDDS causing Retinitis Pigmentosa 59 (0.01033 vs 0.00079), supporting a benign outcome. To our knowledge, no occurrence of c.911C>T in individuals affected with Retinitis Pigmentosa 59 and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as benign.
Ambry Genetics	RCV002540223	SCV003682892	likely benign	Inborn genetic diseases	2022-05-09	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.
Dept Of Ophthalmology, Nagoya University	RCV003890042	SCV004707918	uncertain significance	Retinal dystrophy	2023-10-01	criteria provided, single submitter	research
Natera, Inc.	RCV000904699	SCV001460027	likely benign	Retinitis pigmentosa 59	2020-05-01	no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001355627	SCV001550563	uncertain significance	not provided		no assertion criteria provided	clinical testing	The DHDDS p.Ser303Leu variant was not identified in the literature nor was it identified in ClinVar, Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs141852437) and in control databases in 125 of 282394 chromosomes at a frequency of 0.000443 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: Ashkenazi Jewish in 107 of 10356 chromosomes (freq: 0.01033), Other in 5 of 7214 chromosomes (freq: 0.000693), European (non-Finnish) in 12 of 128826 chromosomes (freq: 0.000093) and African in 1 of 24912 chromosomes (freq: 0.00004), but was not observed in the Latino, East Asian, European (Finnish) or South Asian populations. The p.Ser303 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of 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.
PreventionGenetics, part of Exact Sciences	RCV003932889	SCV004755284	benign	DHDDS-related disorder	2019-07-11	no assertion criteria provided	clinical testing	This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).