rs121909180
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000453.3(SLC5A5):c.1183G>A(p.Gly395Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G395G) has been classified as Likely benign.
Frequency
Consequence
NM_000453.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC5A5 | NM_000453.3 | c.1183G>A | p.Gly395Arg | missense_variant | 10/15 | ENST00000222248.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC5A5 | ENST00000222248.4 | c.1183G>A | p.Gly395Arg | missense_variant | 10/15 | 1 | NM_000453.3 | P1 | |
SLC5A5 | ENST00000597109.1 | n.182G>A | non_coding_transcript_exon_variant | 1/4 | 4 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000398 AC: 10AN: 251436Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135906
GnomAD4 exome AF: 0.0000109 AC: 16AN: 1461860Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727230
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152084Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74278
ClinVar
Submissions by phenotype
Familial thyroid dyshormonogenesis 1 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 20, 2023 | Variant summary: SLC5A5 c.1183G>A (p.Gly395Arg) results in a non-conservative amino acid change in 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 4e-05 in 251436 control chromosomes. c.1183G>A has been reported in the literature in ten homozygous individuals from a large consanguineous family with Familial thyroid dyshormonogenesis 1 (Kosugi_1999). Five of these patients were confirmed to have complete Iodine transport defect. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 10487695). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1999 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 03, 2024 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 395 of the SLC5A5 protein (p.Gly395Arg). This variant is present in population databases (rs121909180, gnomAD 0.009%). This missense change has been observed in individual(s) with SLC5A5-related conditions (PMID: 10487695, 30240412, 33692749). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 7670). 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 SLC5A5 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects SLC5A5 function (PMID: 10487695). For these reasons, this variant has been classified as Pathogenic. - |
Congenital hypothyroidism Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Polak associated Lab, IMAGINE Institute | - | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at