17-80210802-C-T

Variant names:

• chr17-80210802-C-T
• rs62620232
• NM_000199.5:c.1159G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000199.5(SGSH):​c.1159G>A​(p.Val387Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.011 in 1,614,012 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V387L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.010 (16 hom., cov: 33)
  • Exomes 𝑓: 0.011 (173 hom.)
• Consequence: SGSH NM_000199.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 1.19
• Publications: 21 publications found

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]

CARD14 Gene-Disease associations (from GenCC):

• familial pityriasis rubra pilaris

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
• psoriasis 2

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 13 uncertain in NM_000199.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.011575401).
• BP6: Variant 17-80210802-C-T is Benign according to our data. Variant chr17-80210802-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 92609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.01 (1525/152266) while in subpopulation SAS AF = 0.0337 (162/4814). AF 95% confidence interval is 0.0294. There are 16 homozygotes in GnomAd4. There are 824 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000199.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	NM_000199.5	MANE Select	c.1159G>A	p.Val387Met	missense	Exon 8 of 8	NP_000190.1
	SGSH	NR_148201.2		n.1073G>A		non_coding_transcript_exon	Exon 7 of 7
	SGSH	NM_001352921.3		c.*246G>A		3_prime_UTR	Exon 8 of 8	NP_001339850.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SGSH	ENST00000326317.11	TSL:1 MANE Select	c.1159G>A	p.Val387Met	missense	Exon 8 of 8	ENSP00000314606.6
	SGSH	ENST00000575282.5	TSL:1	n.4042G>A		non_coding_transcript_exon	Exon 5 of 5
	SGSH	ENST00000573150.5	TSL:2	n.*369G>A		non_coding_transcript_exon	Exon 7 of 7	ENSP00000459280.1

Frequencies

GnomAD3 genomes AF: 0.0100 AC: 1526 AN: 152148 Hom.: 16 Cov.: 33

Gnomad AFR AF: 0.00162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0314

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0340

Gnomad FIN AF: 0.0210

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0107

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.0134 AC: 3362 AN: 251062 AF XY: 0.0151

Gnomad AFR exome AF: 0.00179

Gnomad AMR exome AF: 0.00630

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0236

Gnomad NFE exome AF: 0.0114

Gnomad OTH exome AF: 0.0132

GnomAD4 exome AF: 0.0111 AC: 16287 AN: 1461746 Hom.: 173 Cov.: 34 AF XY: 0.0122 AC XY: 8877 AN XY: 727164

African (AFR) AF: 0.00167 AC: 56 AN: 33480

American (AMR) AF: 0.00671 AC: 300 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 690 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0335 AC: 2890 AN: 86258

European-Finnish (FIN) AF: 0.0216 AC: 1152 AN: 53284

Middle Eastern (MID) AF: 0.0194 AC: 112 AN: 5768

European-Non Finnish (NFE) AF: 0.00927 AC: 10311 AN: 1112006

Other (OTH) AF: 0.0128 AC: 774 AN: 60390

GnomAD4 genome AF: 0.0100 AC: 1525 AN: 152266 Hom.: 16 Cov.: 33 AF XY: 0.0111 AC XY: 824 AN XY: 74436

African (AFR) AF: 0.00164 AC: 68 AN: 41546

American (AMR) AF: 0.0132 AC: 202 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0314 AC: 109 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0337 AC: 162 AN: 4814

European-Finnish (FIN) AF: 0.0210 AC: 223 AN: 10610

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0107 AC: 730 AN: 68022

Other (OTH) AF: 0.00992 AC: 21 AN: 2116

Alfa AF: 0.0100 Hom.: 32

Bravo AF: 0.00779

TwinsUK AF: 0.00944 AC: 35

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0106 AC: 91

ExAC AF: 0.0132 AC: 1607

Asia WGS AF: 0.00953 AC: 33 AN: 3478

EpiCase AF: 0.0121

EpiControl AF: 0.0118

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Sep 27, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SGSH: PM5, BP4, BS1, BS2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:4

Oct 23, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 30, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Dec 10, 2021

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mucopolysaccharidosis, MPS-III-A Benign:4

Nov 07, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2019

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.056
Eigen_PC	Benign	-0.027
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.014	D
Polyphen		0.90	P
Vest4		0.12
MPC		0.50
ClinPred		0.030	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.69
Mutation Taster		=93/7	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs62620232; hg19: chr17-78184601; COSMIC: COSV58339355; COSMIC: COSV58339355;