Submissions for variant NM_152419.3(HGSNAT):c.1880A>G (p.Tyr627Cys)

gnomAD frequency: 0.00082  dbSNP: rs192857413

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000478941	SCV000568710	uncertain significance	not provided	2022-07-30	criteria provided, single submitter	clinical testing	Reported homozygous in two unrelated patients with mucopolysaccharidosis IIIC, however both patients were also homozygous for a second HGSNAT variant (Ouesleti et al., 2011); Identified homozygous in a patient with tall stature and macroglossia, with normal enzyme studies and normal urine glycosaminoglycans, who was not thought to have MPSIIIC (Deden et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22908982, 21910976, 29870682)
Invitae	RCV000802522	SCV000942357	likely benign	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2024-01-31	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625332	SCV001326458	uncertain significance	Mucopolysaccharidosis, MPS-III-C	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002271509	SCV002555857	likely benign	not specified	2022-06-13	criteria provided, single submitter	clinical testing	Variant summary: HGSNAT c.1880A>G (p.Tyr627Cys) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00069 in 219148 control chromosomes (gnomAD), predominantly at a frequency of 0.0023 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in HGSNAT causing Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C, 0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1880A>G has been reported in the literature in three homozygous individuals affected with Mucopolysaccharidosis Type IIIC (Sanfilippo Syndrome C), however these three individuals were also homozygous for a truncting HGSNAT variant (c.1209G>A, p.Trp403Ter), providing supporting evidence for a benign role (Ouesleti_2011). The variant of interest was also identified in the homozygous state in an unaffected individual (Dedan_2018), providing additional evidence that the variant of interest is not the cause of MPSIIIC in patients reported by Ouesleti_2011. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four ClinVar submitters have assessed the variant since 2014: three classified the variant as of uncertain significance and one as likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Ambry Genetics	RCV002526563	SCV003682201	likely benign	Inborn genetic diseases	2022-03-04	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: 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.
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001252520	SCV001428277	uncertain significance	Intellectual disability	2019-01-01	no assertion criteria provided	clinical testing