Same Variant, Different Notation — Is One of Them Wrong? | HGVS Notation, Part 2

In the previous post, we looked at how to read HGVS notation such as NM_000277.3:c.1222C>T.

But when you compare a variant on a genetic test report against other sources, you may run into something like this.

NM_000277.3:c.1222C>T

NC_000012.12:g.102840493G>A

They’re said to be the same variant, yet the numbers differ, and one shows C>T while the other shows G>A.

The genomic position of the same variant may also appear in one place as

12-103234271-G-A

and elsewhere as

12-102840493-G-A

Is one of them wrong?

No.

The same variant can be written differently depending on the genome build, the transcript, and the reference sequence used to describe it.

In this post, we’ll walk through three common cases where the same variant looks different.

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Why do the GRCh37 and GRCh38 coordinates differ for the same variant?

Let’s start with a variant in the PAH gene.

GRCh37

12-103234271-G-A

GRCh38

12-102840493-G-A

The numbers differ, but they represent the same single variant.

GRCh37 and GRCh38 are different versions of the human reference genome.

Think of it as finding the same place on two different versions of a map.

Because the reference map has changed, the genomic position of the same variant can differ.

So when you check a genomic position, don’t look at the coordinate alone — also confirm whether it’s GRCh37 or GRCh38.

And because how much a coordinate shifts between genome builds varies by position, you must not convert it by simply adding or subtracting numbers.

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Why does the number after c. differ for the same gene?

This time, let’s look at a variant in MECP2.

The same genomic variant can be expressed differently depending on the transcript.

NM_004992.4:c.502C>T

or

NM_001110792.2:c.538C>T

c.502C>T and c.538C>T.

Because the numbers differ, they look like different variants — but they are the same genomic variant described using different transcripts.

A single gene can have multiple transcripts, and the c. position is defined relative to a particular transcript.

So if the reference transcript changes, the number after c. can change even for the same variant.

That’s why, as we saw in Part 1, rather than checking only

c.502C>T

it’s important to check it together with the leading NM_ accession and version, as in

NM_004992.4:c.502C>T

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Why does the same variant appear as G>A in one place and C>T in another?

This time it’s not the numbers but the base change that looks different.

Let’s revisit the PAH variant.

Genomic (g.)

NC_000012.12:g.102840493G>A

Transcript (c.)

NM_000277.3:c.1222C>T

The same variant shows G>A on one side and C>T on the other.

It’s not a typo.

The two strands of DNA are made of complementary bases.

A ↔ T

G ↔ C

For a gene on the minus strand, like PAH, the transcript is oriented in the opposite direction from the genomic reference sequence. As a result, the same variant can be described using complementary bases.

So you shouldn’t conclude that two notations are different variants just because the bases look different between g. and c.

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If the same variant is written differently, what should you check?

To sum up, there are three things to check.

1. Is the genome build the same?

Between GRCh37 and GRCh38, the genomic position of the same variant can differ.

2. Is the transcript the same?

If the NM_ accession differs, the c. position can differ even for the same genomic variant.

3. Is the reference sequence the same?

When a variant is described at different sequence levels — such as g. and c. — both the position and the bases shown can differ.

The most important thing is not to directly match or convert numbers or bases simply because the notation differs.

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This is all you really need to remember

The same variant isn’t always displayed in the same form.

If the genome build changes, the genomic position can change,

if the transcript changes, the number after c. can change,

and if the coordinate system changes — as between genomic DNA and coding DNA — the base change can look different too.

So when you come across two different variant notations, rather than comparing the numbers alone, it’s important to first check which reference each notation is based on.

The variant is the same, but it can have more than one address.

Keep this principle in mind, and notations that look different from one another become easier to make sense of.