Submissions for variant NM_152419.3(HGSNAT):c.1348del (p.Asp450fs)

gnomAD frequency: 0.00001  dbSNP: rs771455190

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001387361	SCV001587975	pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2024-10-03	criteria provided, single submitter	clinical testing	This sequence change creates a premature translational stop signal (p.Asp450Ilefs*32) in the HGSNAT gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HGSNAT are known to be pathogenic (PMID: 17033958, 19479962). This variant is present in population databases (rs771455190, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with mucopolysaccharidosis type IIIC (PMID: 28397838, 31228227). ClinVar contains an entry for this variant (Variation ID: 1074147). For these reasons, this variant has been classified as Pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV001387361	SCV002810897	pathogenic	Mucopolysaccharidosis, MPS-III-C; Retinitis pigmentosa 73	2021-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV003106224	SCV003762019	pathogenic	not provided	2023-01-30	criteria provided, single submitter	clinical testing	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 19479962, 17033958, 28397838, 34374989, 31228227)
Revvity Omics, Revvity	RCV003106224	SCV003822750	pathogenic	not provided	2022-05-11	criteria provided, single submitter	clinical testing
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV001826176	SCV004847312	pathogenic	Mucopolysaccharidosis, MPS-III-C	2023-08-28	criteria provided, single submitter	clinical testing	The p.Asp450IlefsX32 variant in HGSNAT has been reported in 3 homozygous individuals with Mucopolysaccharidosis type IIIC (Martins 2019 PMID: 31228227; Saleh 2021 PMID: 34374989). It has also been identified in 0.005% (2/41424) of African/African-American chromosomes by gnomAD (http://gnomad.broadinstitute.org, v.3.1.2). However, this frequency is low enough to be consistent with a recessive allele frequency. This variant has also been reported in ClinVar (Variation ID 1074147). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 450 and leads to a premature termination codon 32 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the HGSNAT gene is an established disease mechanism in autosomal recessive Mucopolysaccharidosis type IIIC (Hrebicek 2006 PMID: 17033958; Feldhammer 2009 PMID: 19479962). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Mucopolysaccharidosis type IIIC. ACMG/AMP Criteria applied: PVS1, PM3, PM2_Supporting
Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	RCV001826176	SCV005420839	pathogenic	Mucopolysaccharidosis, MPS-III-C	2024-10-04	criteria provided, single submitter	research	PVS1,PM2,PP1,PM3
Natera, Inc.	RCV001826176	SCV002083314	pathogenic	Mucopolysaccharidosis, MPS-III-C	2021-03-28	no assertion criteria provided	clinical testing