TSHR rs1991517: Understanding the Asp727Glu Variant
The rs1991517 variant is a common genetic polymorphism located in the TSHR gene, which encodes the thyroid-stimulating hormone receptor. Research has investigated its potential associations with thyroid hormone levels, bone mineral density, and an increased risk for congenital hypothyroidism.
What each genotype means
Typical thyroid and bone profile
You carry two copies of the common C allele (often noted as Asp727 in the literature). Research links this genotype with baseline circulating thyroid-stimulating hormone (TSH) levels and typical bone mineral density compared to carriers of the alternative allele. Evidence regarding overall risk for thyroid disorders or bone changes remains modest and shows variable results across populations.
Carried by approximately 65% to 80% of individuals across European and global populations.
Moderately altered TSH and BMD profile
You carry one copy of the G allele (corresponding to the Glu727 missense change). Observational studies suggest that carrying a single G allele is associated with slightly lower circulating TSH levels and modest differences in bone mineral density. The biological impact of this single variant is subtle and should be evaluated alongside comprehensive lifestyle, nutrition, and standard clinical markers.
Carried by roughly 15% to 30% of individuals in most populations, including those of European ancestry.
Altered TSH regulation and bone profile
You carry two copies of the less common G allele (Glu727 homozygote). Scientific studies have associated this genotype with genetically lower baseline TSH levels, subtle alterations in thyroid responsiveness, and potential differences in bone mineral density. Because scientific findings remain mixed and effect sizes are small, this genetic variant alone does not diagnose thyroid disease or osteoporosis.
Carried by fewer than 5% of individuals worldwide, representing the least common genotype for this variant.
What is rs1991517?
The rs1991517 variant is a single nucleotide polymorphism (SNP) found within the TSHR gene on chromosome 14. In scientific literature, this variant is frequently referred to as the p.Asp727Glu (or D727E) polymorphism, which describes a specific amino acid change in the resulting protein. Specifically, it involves a substitution where the amino acid aspartic acid (Asp) is replaced by glutamic acid (Glu) at position 727 of the TSH receptor protein. This change occurs in the C-terminus cytoplasmic region of the receptor, a part of the protein involved in signaling pathways. Because this variant is relatively common in many populations, it has been the subject of numerous studies aiming to understand how subtle changes in receptor structure might influence the body's complex thyroid hormone feedback loops.
The Role of the TSHR Gene
The TSHR gene provides instructions for making the thyroid-stimulating hormone receptor, a protein found primarily on the surface of thyroid cells. This receptor acts as a sensor, detecting thyroid-stimulating hormone (TSH) produced by the pituitary gland. When TSH binds to this receptor, it triggers the thyroid gland to produce and release thyroid hormones, which are essential for regulating metabolism, growth, and energy balance. Because the TSH receptor is central to this feedback system, any variation in the gene that alters the receptor's sensitivity or signaling efficiency could theoretically impact thyroid function. Scientists study variants like rs1991517 to determine if they contribute to inter-individual differences in thyroid hormone levels or susceptibility to thyroid-related conditions.
Research and Evidence Strength
Evidence regarding the clinical impact of rs1991517 is considered limited and sometimes conflicting. Some studies have reported an association between the variant and an increased risk for congenital hypothyroidism, with meta-analyses suggesting that the G-allele may be associated with a higher risk in certain populations. Other research has explored its link to serum TSH levels and bone mineral density, though findings have not been consistent across all ethnic groups. For instance, while some studies in smaller cohorts have suggested links to thyroid conditions, these associations are often not replicated in larger, diverse European Caucasian cohorts. The lack of consistency in the literature is likely due to factors such as population stratification, differences in genetic background, and the complex, polygenic nature of thyroid regulation. Consequently, this variant is generally viewed as a research-level marker rather than a definitive diagnostic tool.
Population Frequency
The rs1991517 variant is quite common, with the minor allele frequency (the G-allele) reported at approximately 0.48 in many European populations. This means that the variant is present in a significant portion of the general population, rather than being a rare mutation. Because it is so common, it is often categorized as a polymorphism—a natural variation—rather than a rare disease-causing mutation. However, frequencies can vary significantly depending on ancestral background, and researchers often emphasize that population-specific data is necessary to understand the distribution of this variant globally. Its high prevalence in healthy individuals underscores the fact that carrying the variant does not automatically result in a clinical thyroid condition.
Interpreting Genetic Information
It is important to understand that genetic variants like rs1991517 represent only one small piece of a much larger biological puzzle. Thyroid function is influenced by a combination of many genes, environmental factors, and lifestyle variables. Having a specific genotype for this SNP does not constitute a medical diagnosis, nor does it predict a specific health outcome. If you have concerns about your thyroid health, such as symptoms of fatigue, weight changes, or abnormal blood test results, you should consult a healthcare professional. They can order appropriate clinical tests, such as serum TSH or free T4 levels, which provide a direct measure of your thyroid function. Never use genetic information to make decisions about medication or treatment; always discuss your health concerns and any genetic test results with your doctor or a qualified genetic counselor.
How common is this variant?
The minor allele frequency is approximately 0.48 in European populations, making this a very common genetic variant.
Frequently asked questions
Does the rs1991517 variant cause hypothyroidism?
No, this variant is not considered a direct cause of hypothyroidism. While some research has explored statistical associations between this SNP and thyroid conditions, it is a common polymorphism found in many healthy individuals.
Should I get tested for the TSHR rs1991517 variant?
There is generally no clinical utility in testing for this specific variant for diagnostic purposes. Thyroid health is best assessed through standard blood tests ordered by a physician, such as TSH and thyroid hormone levels.
Can this variant affect my thyroid medication dosage?
There is no current clinical evidence or guideline suggesting that this variant should influence thyroid medication dosing. If you have questions about your medication, you must discuss them with your clinician or pharmacist.
Is rs1991517 the same as a TSHR mutation?
While it is a change in the DNA sequence, it is classified as a polymorphism because it is common in the population. In contrast, rare TSHR mutations that cause severe congenital hypothyroidism are typically distinct from this common variant.
Sources & further reading
Educational information only, last refreshed 10/26/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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