DHCR7 rs28941772: Understanding the c.964-1G>C Variant
The DHCR7 variant rs28941772, also known as c.964-1G>C, is a pathogenic genetic change located in the DHCR7 gene. It is primarily associated with Smith-Lemli-Opitz syndrome, an autosomal recessive condition that affects the body's ability to produce cholesterol.
What each genotype means
Typical risk
You carry two reference copies of this DHCR7 locus and do not carry the c.964-1G>C pathogenic splice variant. This result indicates you are not a carrier for this specific cause of Smith-Lemli-Opitz syndrome. Because carrier screening evaluates specific variants, it does not completely eliminate the possibility of rare, unassayed variants elsewhere in the DHCR7 gene.
Carried by over 98% to 99% of people across most global populations.
SLOS carrier status
You carry one copy of the pathogenic c.964-1G>C (IVS8-1G>C) variant, making you an asymptomatic carrier of autosomal recessive Smith-Lemli-Opitz syndrome. Carriers do not experience classic symptoms of the disorder, as one functional copy of the DHCR7 gene typically maintains sufficient enzyme activity. Reproductive risk is primarily relevant if your partner is also a carrier for a pathogenic DHCR7 variant, which can be evaluated through reproductive genetic counseling.
Carried by approximately 1% to 2% of individuals of European ancestry and around 0.7% of African Americans; it is much less common in East Asian populations.
High risk for SLOS
This genotype indicates two copies of the c.964-1G>C null splice variant in DHCR7, a pattern strongly associated with Smith-Lemli-Opitz syndrome. In medical literature, homozygosity for this severe variant disrupts cholesterol biosynthesis and is associated with severe multi-system congenital features or high early mortality. Clinical confirmation and consultation with a medical geneticist are essential to contextualize these genetic findings.
Extremely rare across all populations, occurring in fewer than 1 in 100,000 individuals globally.
What is the rs28941772 Variant?
The variant rs28941772, technically described as c.964-1G>C, is a specific change in the DNA sequence of the DHCR7 gene. It is located in an intron, which is a non-coding region of the gene, specifically at a splice site. Splice sites are critical junctions that tell the cell how to correctly assemble the messenger RNA (mRNA) instructions for building a protein. When a mutation occurs at this junction, it can cause the cell to skip an exon or include incorrect sequences, leading to a non-functional or absent protein. This specific G-to-C substitution is recognized as a null mutation, meaning it effectively prevents the production of the functional enzyme that the gene is supposed to create.
The Role of the DHCR7 Gene
The DHCR7 gene provides instructions for making an enzyme called 7-dehydrocholesterol reductase. This enzyme is the final step in the body's cholesterol biosynthesis pathway, responsible for converting 7-dehydrocholesterol into cholesterol. Cholesterol is a vital molecule, essential for the structure of cell membranes and the production of hormones, bile acids, and vitamin D. When the DHCR7 enzyme is deficient or absent due to pathogenic variants, 7-dehydrocholesterol accumulates in the body's tissues and blood, while cholesterol levels may be abnormally low. This imbalance is the underlying cause of Smith-Lemli-Opitz syndrome (SLOS), a developmental disorder that can affect multiple organ systems, including the brain, heart, and limbs.
Research and Clinical Significance
Research has established rs28941772 as one of the most common pathogenic variants associated with Smith-Lemli-Opitz syndrome, particularly in populations of European descent. Because SLOS is an autosomal recessive disorder, an individual must inherit two pathogenic variants—one from each parent—to be affected. Individuals who carry only one copy of this variant are typically asymptomatic carriers. Clinical studies have observed that individuals who are homozygous for this null variant (having two copies) often exhibit a severe phenotype. However, because most affected individuals are compound heterozygotes (carrying two different pathogenic variants), the clinical presentation can vary significantly. It is important to note that genotype-phenotype correlations are complex, and the presence of this variant alone does not dictate the exact severity of the condition.
Population Frequency
The frequency of the rs28941772 variant varies by ancestry, with higher carrier rates observed in certain European populations. For example, studies have reported carrier frequencies ranging from 0.2% to 2.3% in various European cohorts, including German, Polish, and Czech populations. While it is considered rare in the general global population (gnomAD frequency < 0.01%), it remains a significant founder variant in specific regions. Because it is a recessive condition, the risk of having an affected child is primarily a concern for couples where both partners are identified as carriers through genetic screening. If you have concerns about your carrier status or family history, it is recommended to consult with a genetic counselor or a medical professional who can provide context based on your specific background.
What You Can Do With This Information
Genetic information regarding carrier status is intended for educational and reproductive planning purposes. If you have received a report indicating you are a carrier for this variant, it does not mean you have the disease, but it does mean there is a possibility of passing the variant to your children. If your partner is also a carrier, there is a 25% chance for each pregnancy to result in a child with Smith-Lemli-Opitz syndrome. This information should never be used to self-diagnose or make medical decisions without professional guidance. Always discuss your genetic results with a qualified clinician or a board-certified genetic counselor. They can help you understand the implications, discuss testing options for your partner, and provide appropriate support for family planning.
How common is this variant?
The variant is rare in the general population (gnomAD < 0.01%), though carrier frequencies in specific European populations have been reported between 0.2% and 2.3%.
Frequently asked questions
What is Smith-Lemli-Opitz syndrome?
Smith-Lemli-Opitz syndrome (SLOS) is a rare, inherited disorder caused by a deficiency in the enzyme that produces cholesterol. It can lead to physical, behavioral, and developmental challenges.
If I am a carrier, will my children have the syndrome?
Being a carrier means you have one copy of the variant. If your partner is not a carrier, your children will not have the syndrome, though they may also be carriers. If your partner is also a carrier, there is a 25% chance for each child to inherit two copies and be affected.
Is there a cure for SLOS?
There is currently no cure for SLOS. Management typically involves dietary cholesterol supplementation and other supportive therapies to address specific symptoms, which should be managed by a specialized medical team.
Should I get tested for this variant?
Carrier screening is often recommended for individuals with a family history of SLOS or those planning a pregnancy who wish to understand their reproductive risks. Discuss the necessity of testing with your doctor or a genetic counselor.
Sources & further reading
Educational information only, last refreshed 10/29/2026. Not medical advice — these associations describe population statistics, not individual predictions.
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