Variants of Uncertain Significance in Alström Testing

When a genetic test report comes back with a "variant of uncertain significance" — a VUS — most families feel anything but reassured. The result isn't a clear yes, isn't a clear no, and offers no guidance about next steps without help. This article explains what a VUS actually is in ALMS1 testing, why labs report them, and what families can do to get more clarity.

A VUS is a genetic change found in a person's DNA where the available evidence isn't sufficient to classify it as either disease-causing or harmless. Labs use a standardized framework — typically the American College of Medical Genetics and Genomics (ACMG) variant interpretation guidelines — to classify variants into five tiers:¹

1. Pathogenic — disease-causing 2. Likely pathogenic — strong evidence of being disease-causing 3. Variant of uncertain significance (VUS) — evidence is mixed or limited 4. Likely benign — strong evidence of being harmless 5. Benign — known to be harmless

A VUS isn't an indictment and isn't an exoneration. It's a holding pattern.

Several factors contribute to a variant being labeled VUS:

• The variant has not been seen before in the lab's databases or in publicly accessible variant databases (ClinVar, gnomAD, etc.)
• Computational tools give mixed predictions about whether the variant disrupts function
• The variant doesn't clearly segregate with disease in the family
• Functional studies don't yet exist for that specific change

VUSs are particularly common in large genes like ALMS1, where many possible changes exist and only a subset have been thoroughly studied.

Common VUS scenarios include:

• A missense change at a location not previously linked to Alström, where computational tools disagree about likely impact
• A change in a non-canonical splice site where the impact on splicing is unclear
• A small in-frame deletion that may or may not disrupt function
• A change found in some healthy people in databases but at a frequency that doesn't fully rule out pathogenicity

The lab report will give a brief justification for the VUS classification, citing the evidence considered.

A VUS isn't the end of the story. Several steps can help reclassify it:

Parental segregation testing

If your child has a VUS plus a clearly pathogenic variant, testing the parents shows whether the VUS came from the same parent as the pathogenic variant or from the other parent. If the VUS is from the parent who didn't transmit the pathogenic variant, that's evidence the VUS is on the trans (other) allele — supporting biallelic inheritance and pathogenicity.

If the VUS is from the same parent as the pathogenic variant, both variants are on the same chromosome and the child has only one functional disease allele — meaning a different cause of disease should be sought, or the second pathogenic variant hasn't been found yet.²

Reanalysis after time

VUSs are routinely reclassified — sometimes upward (pathogenic), sometimes downward (benign), sometimes still uncertain — as new families with the same variant emerge in the literature and databases. Asking your geneticist to request a reanalysis every 12–24 months can return updated information.

Functional studies

For some VUSs, research labs may be willing to perform functional studies that test whether the protein product behaves abnormally. This is uncommon outside of research settings but possible in some academic centers.

Search public databases yourself or with your counselor

ClinVar, the public database of variant interpretations, may show that another lab has classified the same variant differently. Knowing of disagreement can prompt re-examination.

Consider expanded testing

If the diagnosis is in doubt because of the VUS, expanding to whole-exome sequencing may reveal an alternative explanation — a different ciliopathy or a different condition altogether.

Some families find themselves in a holding pattern — clinical features suggest Alström, but the genetic test isn't definitive. Several practical considerations:

Surveillance based on clinical findings, not on the genetic test

If your child has clinical features of Alström, surveillance for cardiac, audiologic, ophthalmologic, and metabolic complications is appropriate regardless of whether the genetic diagnosis is fully confirmed.

Recurrence risk discussions are more nuanced

When a VUS is involved, the genetic counselor will frame recurrence risk in conditional terms — "if the VUS turns out to be pathogenic, the recurrence risk is 25%; if it turns out to be benign, the risk is much lower."

Insurance and benefits may be affected

Some benefits programs require a confirmed genetic diagnosis. A pending VUS classification may complicate access. Documentation from your geneticist explaining the clinical diagnosis pending genetic confirmation can help.

Connect with your patient organization

Patient organizations sometimes know of other families with the same VUS and may be able to facilitate communication or research participation that helps the broader interpretation effort.

• Alström Syndrome Genetics: ALMS1 Gene Explained
• Genetic Testing for Alström Syndrome: A Parent's Guide
• ALMS1 Mutations: Understanding Your Genetic Test Report
• Genetic Counseling for Alström Syndrome Families

April 30, 2026.