NM_000199.5:c.673T>C

Variant names:

• chr17-80213876-A-G
• rs1057521801
• NM_000199.5:c.673T>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_000199.5(SGSH):​c.673T>C​(p.Phe225Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 8.72

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]

CARD14 (HGNC:16446): (caspase recruitment domain family member 14) This gene encodes a caspase recruitment domain-containing protein that is a member of the membrane-associated guanylate kinase (MAGUK) family of proteins. Members of this protein family are scaffold proteins that are involved in a diverse array of cellular processes including cellular adhesion, signal transduction and cell polarity control. This protein has been shown to specifically interact with BCL10, a protein known to function as a positive regulator of cell apoptosis and NF-kappaB activation. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.909
• PP5: Variant 17-80213876-A-G is Pathogenic according to our data. Variant chr17-80213876-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 383967.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SGSH	NM_000199.5	c.673T>C	p.Phe225Leu	missense_variant	Exon 6 of 8	ENST00000326317.11	NP_000190.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SGSH	ENST00000326317.11	c.673T>C	p.Phe225Leu	missense_variant	Exon 6 of 8	1	NM_000199.5	ENSP00000314606.6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455688 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 724088

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Mucopolysaccharidosis, MPS-III-A Pathogenic:3

Feb 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 225 of the SGSH protein (p.Phe225Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with mucopolysaccharidosis type III (PMID: 21204211). ClinVar contains an entry for this variant (Variation ID: 383967). 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. 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. -

Apr 26, 2017

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The following ACMG criteria are met: PS1 (Same amino acid change as pathogenic variant, Heron 2010), PS3 (Well-established functional study), PM2 (Absent from population databases), PM3 (In trans with pathogenic variant), PP1 (Co-segregation with disease in multiple family members). Two sisters in our clinical practice are compound heterozygotes for E355K and P225L and a clinical diagnosis of MPS IIIA was confirmed by clinical exam, positive urine screen, and absent enzyme activity in leukocytes. The younger sister has global developmental delays, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, and a seizure disorder. The older sister has intellectual disability, autism spectrum disorder, sensorineural hearing loss, myopia, astigmatism, recurrent otitis media, precocious puberty, and seizure disorder. -

Nov 07, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 31, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.673 T>C nucleotide substitution, resulting in the F225L amino acid change, has not been reported previously as a pathogenic or benign variant to our knowledge. However, a different nucleotide substitution (c.675C>G) that also results in the F225L missense substitution was previously identified in two families with mucopolysaccharidosis type IIIA (MPSIIIA), supporting the functional importance of this position in the protein (Heron et al., 2010). Additionally, a missense variant in a neighboring codon (P227R) has been reported in the Human Gene Mutation Database in association with MPSIIIA (Stenson et al., 2014). The F225L variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. It is a conservative amino acid substitution that occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. The F225L variant is a strong candidate for a pathogenic variant, however the possibility it may be a rare benign variant cannot be excluded. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.46
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.79	D
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	2.0	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.010	D
Sift4G	Benign	0.066	T
Polyphen		0.79	P
Vest4		0.81
MutPred		0.63		Gain of sheet (P = 0.0827);
MVP		0.99
MPC		0.57
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.75
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1057521801; hg19: chr17-78187675;