rs587784384

Positions:

• chrX-74525834-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_006517.5(SLC16A2):​c.1111C>T​(p.Arg371Cys) variant causes a missense change. 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: 23)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 5.76

Genes affected

SLC16A2 (HGNC:10923): (solute carrier family 16 member 2) This gene encodes an integral membrane protein that functions as a transporter of thyroid hormone. The encoded protein facilitates the cellular importation of thyroxine (T4), triiodothyronine (T3), reverse triiodothyronine (rT3) and diidothyronine (T2). This gene is expressed in many tissues and likely plays an important role in the development of the central nervous system. Loss of function mutations in this gene are associated with psychomotor retardation in males while females exhibit no neurological defects and more moderate thyroid-deficient phenotypes. This gene is subject to X-chromosome inactivation. Mutations in this gene are the cause of Allan-Herndon-Dudley syndrome. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a mutagenesis_site Does not affect localization to the cell membrane. Abolishes T3 uptake activity. (size 0) in uniprot entity MOT8_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96
• PP5: Variant X-74525834-C-T is Pathogenic according to our data. Variant chrX-74525834-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74525834-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC16A2	NM_006517.5	c.1111C>T	p.Arg371Cys	missense_variant	4/6	ENST00000587091.6	NP_006508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC16A2	ENST00000587091.6	c.1111C>T	p.Arg371Cys	missense_variant	4/6	1	NM_006517.5	ENSP00000465734	P1
SLC16A2	ENST00000590447.1	c.553C>T	p.Arg185Cys	missense_variant	3/4	5		ENSP00000466213
SLC16A2	ENST00000636771.1	c.*812C>T		3_prime_UTR_variant, NMD_transcript_variant	5/7	5		ENSP00000490445

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Allan-Herndon-Dudley syndrome Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Likely pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Likely Pathogenic, for Allan-Herndon-Dudley syndrome, in X-linked recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PP1 => Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease (PMID:24721225). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Moderate => Functional studies show a deleterious effect. (PMID:24265446,25527620). -

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2019

This variant has been observed in individuals and families affected with clinical features of Allan-Herndon-Dudley syndrome (AHDS) (PMID: 23568789, 24721225). This variant is also known as c.1333C>T, p.Arg445Cys in the literature. ClinVar contains an entry for this variant (Variation ID: 159902). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with cysteine at codon 371 of the SLC16A2 protein (p.Arg371Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant has been reported to affect SLC16A2 protein function (PMID: 23568789, 24265446, 25527620). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg371 amino acid residue in SLC16A2. Other variant(s) that disrupt this residue have been observed in individuals with SLC16A2-related conditions (PMID: 27212794), which suggests that this may be a clinically significant amino acid residue. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2017

- -

Hereditary spastic paraplegia Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 06, 2017

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

May 19, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.72	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.68	T
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.89
MutPred		0.75		Loss of methylation at R371 (P = 0.0162);
MVP		1.0
MPC		2.3
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.80
gMVP		0.97

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: rs587784384; hg19: chrX-73745669; COSMIC: COSV52086067;