ClinVar Miner

Submissions for variant NM_152419.3(HGSNAT):c.1843G>A (p.Ala615Thr) (rs112029032)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 17
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000224674 SCV000280806 likely benign not provided 2015-10-09 criteria provided, single submitter clinical testing Converted during submission to Likely benign.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282689 SCV000603957 likely benign none provided 2020-02-14 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000224674 SCV000609303 uncertain significance not provided 2017-03-01 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000507277 SCV000854858 benign not specified 2017-09-26 criteria provided, single submitter clinical testing
Invitae RCV001082167 SCV001122659 benign Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73 2020-11-26 criteria provided, single submitter clinical testing
Mendelics RCV000190845 SCV001137619 likely benign Mucopolysaccharidosis, MPS-III-C 2019-05-28 criteria provided, single submitter clinical testing
Blueprint Genetics RCV000504631 SCV001240010 pathogenic Retinal dystrophy 2020-05-13 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000190845 SCV001326457 likely benign Mucopolysaccharidosis, MPS-III-C 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000190844 SCV001366988 uncertain significance Retinitis pigmentosa 73 2019-12-17 criteria provided, single submitter clinical testing This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4.
Broad Institute Rare Disease Group, Broad Institute RCV001003049 SCV001950282 likely pathogenic Retinitis pigmentosa 2021-04-01 criteria provided, single submitter curation The p.Ala615Thr variant in HGSNAT was identified in an individual with Retinitis pigmentosa, via a collaborative study between the Broad Institute's Center for Mendelian Genomics and the Pierce lab (https://oculargenomics.meei.harvard.edu/labs/pierce-lab/lab-members/). Through a review of available evidence we were able to apply the following criteria: PS3, PM3. Based on this evidence we have classified this variant as Likely Pathogenic. If you have any questions about the classification please reach out to the Pierce Lab.
GeneDx RCV000224674 SCV001950970 benign not provided 2019-06-25 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 27608171, 25859010, 20583299, 19479962, 19823584, 17033958, 28041643, 29144512, 28981474, 31456290, 32770643, 32581362, 33576794)
OMIM RCV000190844 SCV000245714 pathogenic Retinitis pigmentosa 73 2015-07-01 no assertion criteria provided literature only
OMIM RCV000190845 SCV000245715 pathogenic Mucopolysaccharidosis, MPS-III-C 2015-07-01 no assertion criteria provided literature only
NIHR Bioresource Rare Diseases, University of Cambridge RCV000504631 SCV000599072 likely pathogenic Retinal dystrophy 2015-01-01 no assertion criteria provided research
Sharon lab,Hadassah-Hebrew University Medical Center RCV001003049 SCV001161106 pathogenic Retinitis pigmentosa 2019-06-23 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000224674 SCV001552922 likely benign not provided no assertion criteria provided clinical testing The HGSNAT p.Ala615Thr variant was identified in 2 of 83 families with Mucopolysaccharidosis Type III (freq: 0.012), and was found as a complex allele with the HGSNAT p.W403C variant (Feldhammer_2009_PMID:19479962). Functional studies demonstrate that the p.A615T variant on its own does not affect HGSNAT protein function, however when found with the p.W403C variant there was a loss of HGSNAT protein activity (Feldhammer_2009_PMID:19479962; Fedele_2010_PMID:20583299). The p.A615T variant was also found as a homozygous variant in three affected members of a Dutch family with non-syndromic retinitis pigmentosa; all three affected family members were also heterozygous for another variant in the HGSNAT gene (p.G133A) (Haer-Wigman_2015_PMID:25859010). In a cohort of 722 individuals with inherited retinal disease, the p.A615T variant was identified in two patients with retinal dystrophy (freq: 0.001) (Carss_2017_PMID:28041643). The variant was identified in the following databases: dbSNP (ID: rs112029032), LOVD 3.0 and ClinVar (classified as benign by EGL Genetic Diagnostics, as likely benign by ARUP laboratories and Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics, as uncertain significance by CeGaT Praxis fuer Humangenetik Tuebingen and as likely pathogenic by NIHR Bioresource Rare Diseases, University of Cambridge). The variant was identified in control databases in 1119 of 277692 chromosomes (4 homozygous) at a frequency of 0.00403 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: Ashkenazi Jewish in 148 of 10188 chromosomes (freq: 0.01453), European (non-Finnish) in 691 of 127570 chromosomes (freq: 0.005417), European (Finnish) in 106 of 24896 chromosomes (freq: 0.004258), Other in 28 of 7056 chromosomes (freq: 0.003968), South Asian in 90 of 29666 chromosomes (freq: 0.003034), African in 23 of 24384 chromosomes (freq: 0.000943), Latino in 31 of 34504 chromosomes (freq: 0.000898), and East Asian in 2 of 19428 chromosomes (freq: 0.000103). The p.Ala615 residue is conserved in mammals but not in more distantly related organisms however four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out 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 although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Genomics England Pilot Project,Genomics England RCV000190844 SCV001760216 pathogenic Retinitis pigmentosa 73 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.