rs104894637

Variant names:

• chr17-80217084-G-A
• rs104894637
• NM_000199.5:c.197C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-80217084-G-A
• chr17-80217084-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PM5 PP5

The NM_000199.5(SGSH):​c.197C>T​(p.Ser66Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000759 in 1,448,528 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S66W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000076 (0 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 9.05

Genes affected

SGSH (HGNC:10818): (N-sulfoglucosamine sulfohydrolase) This gene encodes the enzyme sulfamidase; one of several enzymes involved in the lysosomal degradation of heparan sulfate. Mutations in this gene are associated with the lysosomal storage disease mucopolysaccaridosis IIIA, also known as Sanfilippo syndrome A, which results from impaired degradation of heparan sulfate. Transcripts of varying sizes have been reported but their biological validity has not been determined. [provided by RefSeq, Jun 2017]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-80217084-G-C is described in Lovd as [Pathogenic].
• PP5: Variant 17-80217084-G-A is Pathogenic according to our data. Variant chr17-80217084-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1910563.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5	c.197C>T	p.Ser66Leu	missense_variant	Exon 2 of 8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.197C>T	p.Ser66Leu	missense_variant	Exon 2 of 8	1	NM_000199.5	ENSP00000314606.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000442 AC: 1 AN: 226198 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 122814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000179

GnomAD4 exome AF: 0.00000759 AC: 11 AN: 1448528 Hom.: 0 Cov.: 31 AF XY: 0.00000417 AC XY: 3 AN XY: 719644

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000903

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:1

Jun 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 66 of the SGSH protein (p.Ser66Leu). This variant is present in population databases (rs104894637, gnomAD 0.001%). This variant has not been reported in the literature in individuals affected with SGSH-related conditions. ClinVar contains an entry for this variant (Variation ID: 1910563). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SGSH protein function with a positive predictive value of 95%. This variant disrupts the p.Ser66 amino acid residue in SGSH. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9158154, 9285796, 9554748, 15542396, 21061399, 22976768). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

not specified Uncertain:1

Mar 25, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SGSH c.197C>T (p.Ser66Leu) results in a non-conservative amino acid change located in the Sulfatase, N-terminal domain (IPR000917) of 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 4.4e-06 in 226198 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.197C>T in individuals affected with Mucopolysaccharidosis Type IIIA (Sanfilippo Syndrome A) and no experimental evidence demonstrating its impact on protein function have been reported. A different variant affecting this residue has been classified pathogenic internally (p.Ser66Trp), this suggests that this residue may be clinically significant. ClinVar contains an entry for this variant (Variation ID: 1910563). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	33
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.66	D
MetaRNN	Uncertain	0.60	D
MetaSVM	Pathogenic	1.1	D
Sift4G	Uncertain	0.025	D
Vest4		0.30
MVP		0.91
ClinPred		0.98	D
GERP RS		3.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs104894637; hg19: chr17-78190883;