rs199588904
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_198407.2(GHSR):c.709A>T(p.Arg237Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000191 in 1,614,088 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R237K) has been classified as Uncertain significance.
Frequency
Consequence
NM_198407.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GHSR | NM_198407.2 | c.709A>T | p.Arg237Trp | missense_variant | 1/2 | ENST00000241256.3 | |
GHSR | NM_004122.2 | c.709A>T | p.Arg237Trp | missense_variant | 1/1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GHSR | ENST00000241256.3 | c.709A>T | p.Arg237Trp | missense_variant | 1/2 | 1 | NM_198407.2 | P1 | |
GHSR | ENST00000427970.1 | c.709A>T | p.Arg237Trp | missense_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.000105 AC: 16AN: 152078Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.000199 AC: 50AN: 250676Hom.: 0 AF XY: 0.000236 AC XY: 32AN XY: 135634
GnomAD4 exome AF: 0.000201 AC: 294AN: 1461892Hom.: 0 Cov.: 31 AF XY: 0.000215 AC XY: 156AN XY: 727246
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152196Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 4AN XY: 74420
ClinVar
Submissions by phenotype
Short stature due to growth hormone secretagogue receptor deficiency Pathogenic:1Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory of Medical Genetics, National & Kapodistrian University of Athens | Oct 06, 2021 | PM2, PP3, BP1 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | The GHSR c.709A>T (p.Arg237Trp) missense variant was identified in a compound heterozygous state in one individual with short stature and endocrine analysis consistent with partial isolated growth hormone deficiency (Pantel et al. 2009). Family studies revealed that the individual's unaffected mother and an unaffected sibling were heterozygous for the variant. Control data are unavailable for this variant, which is reported at a frequency of 0.00047 in the European-American population of the Exome Sequencing Project. In vitro expression experiments showed that the p.Arg237Trp variant resulted in a partial loss of constitutive activity of the receptor, though the ability to respond to ghrelin and its cell surface expression were preserved. The evidence for this variant is limited. The p.Arg237Trp variant is classified as a variant of unknown significance but suspicious for pathogenicity for partial isolated growth hormone deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
not provided Uncertain:4
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 06, 2019 | In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Observed with a variant on the opposite allele (in trans) in a patient with partial growth hormone deficiency and unexplained episodes of abdominal pain, vomiting, ketosis, and hypoglycemia. Unaffected parents with normal stature were heterozygous carriers (Pantel et al., 2009).; In vitro functional studies show that the R237W mutant has a lower constitutive expression compared to wild type, however, R237W demonstrated normal cell surface expression and a normal ability to bind and respond to ghrelin (Pantel et al., 2009); This variant is associated with the following publications: (PMID: 19789204) - |
Uncertain significance, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 12, 2024 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 237 of the GHSR protein (p.Arg237Trp). This variant is present in population databases (rs199588904, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of growth hormone deficiency (PMID: 19789204). ClinVar contains an entry for this variant (Variation ID: 7634). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GHSR protein function. Experimental studies have shown that this missense change affects GHSR function (PMID: 19789204). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2020 | The alteration results in an amino acid change:_x000D_ _x000D_ The c.709A>T (p.R237W) alteration is located in coding exon 1 of the GHSR gene. This alteration results from a A to T substitution at nucleotide position 709, causing the arginine (R) at amino acid position 237 to be replaced by a tryptophan (W). The alteration is rare in population databases: _x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the c.709A>T alteration was observed in 0.0195% (55/282,042) of total alleles studied. No homozygotes were reported in gnomAD. The alteration has been observed in affected individuals:_x000D_ _x000D_ A 6 year old boy with partial isolated growth hormone deficiency (IGHD) was reported to have compound heterozygous c.709A>T (p.R237W) and c.6G>A (p.W2*) in GHSR (Pantel, 2009). The patient initially had normal birth height and weight. Growth delay (−3.0 SD) was associated with recurrent episodes of abdominal pain, vomiting, ketosis, hypoglycemia, and a low body mass index. Endocrine investigations revealed markedly low levels of IGF-I. He displayed a low growth hormone (GH) response to two provocative tests with GH peaks less than 10 ng/ml and no other pituitary hormone deficiency, consistent with the diagnosis of partial IGHD. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.R237 amino acid is conserved in available vertebrate species. The alteration is predicted inconclusive by in silico modeling:_x000D_ _x000D_ The in silico prediction for the p.R237W alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at