rs587784383

Positions:

• chrX-74524762-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_006517.5(SLC16A2):​c.979G>A​(p.Gly327Arg) 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: 22)
• Consequence: SLC16A2 NM_006517.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.60

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 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-74524762-G-A is Pathogenic according to our data. Variant chrX-74524762-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 159901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-74524762-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SLC16A2	NM_006517.5	c.979G>A	p.Gly327Arg	missense_variant	3/6	ENST00000587091.6	NP_006508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SLC16A2	ENST00000587091.6	c.979G>A	p.Gly327Arg	missense_variant	3/6	1	NM_006517.5	ENSP00000465734	P1
SLC16A2	ENST00000590447.1	c.421G>A	p.Gly141Arg	missense_variant	2/4	5		ENSP00000466213
SLC16A2	ENST00000636771.1	c.*680G>A		3_prime_UTR_variant, NMD_transcript_variant	4/7	5		ENSP00000490445

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spastic paraplegia Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 02, 2023

This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Allan–Herndon–Dudleysyndrome (PMID: 20083155, 23744248, 30369548). This variant is also known as Gly401Arg. ClinVar contains an entry for this variant (Variation ID: 159901). 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 SLC16A2 protein function. Experimental studies have shown that this missense change affects SLC16A2 function (PMID: 30369548). This variant disrupts the p.Gly327 amino acid residue in SLC16A2. Other variant(s) that disrupt this residue have been observed in individuals with SLC16A2-related conditions (PMID: 31410843), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 327 of the SLC16A2 protein (p.Gly327Arg). -

Decreased activity of the pyruvate dehydrogenase complex Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

May 14, 2015

- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Oct 23, 2020

- -

Allan-Herndon-Dudley syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.86	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.81		Gain of MoRF binding (P = 0.0189);
MVP		1.0
MPC		2.2
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.99

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

Publications

LitVar

Other links and lift over

dbSNP: rs587784383; hg19: chrX-73744597;