NM_178138.6:c.920G>C

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_178138.6(LHX3):c.920G>C(p.Arg307Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00138 in 1,548,308 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00074 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

LHX3
NM_178138.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:2

Conservation

PhyloP100: 3.81

Variant links:

Genes affected

LHX3 (HGNC:6595): (LIM homeobox 3) This gene encodes a member of a large family of proteins which carry the LIM domain, a unique cysteine-rich zinc-binding domain. The encoded protein is a transcription factor that is required for pituitary development and motor neuron specification. Mutations in this gene cause combined pituitary hormone deficiency 3. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

LHX3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.014613599).

BP6

Variant 9-136197599-C-G is Benign according to our data. Variant chr9-136197599-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 279837.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}. Variant chr9-136197599-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000742 (113/152222) while in subpopulation NFE AF= 0.0014 (95/67986). AF 95% confidence interval is 0.00117. There are 0 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX3	NM_178138.6 link	c.920G>C	p.Arg307Pro	missense_variant	Exon 6 of 6	ENST00000371748.10	NP_835258.1	Q9UBR4-1F1T0D5
LHX3	NM_014564.5 link	c.935G>C	p.Arg312Pro	missense_variant	Exon 6 of 6		NP_055379.1	Q9UBR4-2F1T0D9
LHX3	NM_001363746.1 link	c.887G>C	p.Arg296Pro	missense_variant	Exon 6 of 6		NP_001350675.1
LHX3	XM_017015168.1 link	c.848G>C	p.Arg283Pro	missense_variant	Exon 6 of 6		XP_016870657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LHX3	ENST00000371748.10 link	c.920G>C	p.Arg307Pro	missense_variant	Exon 6 of 6	1	NM_178138.6	ENSP00000360813.4	Q9UBR4-1
LHX3	ENST00000371746.9 link	c.935G>C	p.Arg312Pro	missense_variant	Exon 6 of 6	1		ENSP00000360811.3	Q9UBR4-2
LHX3	ENST00000619587.1 link	c.887G>C	p.Arg296Pro	missense_variant	Exon 6 of 6	1		ENSP00000483080.1	F1T0D7
LHX3	ENST00000645419.1 link	n.1745G>C		non_coding_transcript_exon_variant	Exon 5 of 5

Frequencies

GnomAD3 genomes

AF:

0.000743

AC:

113

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00140

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000652

AC:

AN:

151868

Hom.:

AF XY:

0.000557

AC XY:

AN XY:

82636

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000818

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000763

Gnomad NFE exome

AF:

0.00134

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00145

AC:

2021

AN:

1396086

Hom.:

Cov.:

AF XY:

0.00145

AC XY:

998

AN XY:

687896

show subpopulations

Gnomad4 AFR exome

AF:

0.000126

Gnomad4 AMR exome

AF:

0.000790

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000220

Gnomad4 NFE exome

AF:

0.00179

Gnomad4 OTH exome

AF:

0.000952

GnomAD4 genome

AF:

0.000742

AC:

113

AN:

152222

Hom.:

Cov.:

AF XY:

0.000645

AC XY:

AN XY:

74420

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00140

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000672

Hom.:

Bravo

AF:

0.000718

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00108

AC:

ExAC

AF:

0.000321

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Mar 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 312 of the LHX3 protein (p.Arg312Pro). This variant is present in population databases (rs182345541, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with LHX3-related conditions. ClinVar contains an entry for this variant (Variation ID: 279837). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). 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. -

Jul 20, 2016

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The R312P variant in the LHX3 gene has been reported previously in one individual with pituitary aplasia; however, no second LHX3 variant was identified, and R312P was also present in the heterozygous state in this individual's unaffected father and sister (Sobrier et al., 2006). The R312P variant was not observed at any significant frequency in approximately 6300 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The R312P variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis predicts this variant likely does not alter the protein structure/function. We interpret R312P as a variant of uncertain significance. -

Non-acquired combined pituitary hormone deficiency with spine abnormalities

Uncertain:1Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

LHX3-related disorder

Uncertain:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The LHX3 c.935G>C variant is predicted to result in the amino acid substitution p.Arg312Pro. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.13% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Combined pituitary hormone deficiencies, genetic form

Uncertain:1

Dec 24, 2019

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Nov 27, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LHX3 c.935G>C (p.Arg312Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 1541942 control chromosomes, predominantly at a frequency of 0.0018 within the Non-Finnish European subpopulation in the gnomAD database (v4.1 dataset), including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.44-fold of the estimated maximal expected allele frequency for a pathogenic variant in LHX3 causing Combined Pituitary Hormone Deficiency phenotype (0.0013). The variant, c.935G>C, has been reported in the literature in heterozygous state in individuals affected with Combined Pituitary Hormone Deficiency, however it was also found in unaffected family members, and unrelated healthy controls (Sobrier_2006, de Graaff_2010), in addition, one of the reported patients also had a biallelic loss of function variant in a different gene, which could potentially explain the phenotype (Sobrier_2006). One of these studies also reported no effect for the variant on the transcriptional capability of the LHX3 protein, but no experimental details were provided for independent evaluation (Sobrier_2006). The following publications have been ascertained in the context of this evaluation (PMID: 16940453, 20389107). ClinVar contains an entry for this variant (Variation ID: 279837). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.60

DEOGEN2

Benign

0.21

.;T;.

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.84

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

T;T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.2

.;L;.

PrimateAI

Benign

0.44

PROVEAN

Benign

0.76

N;N;.

REVEL

Uncertain

0.31

Sift

Benign

0.51

T;T;.

Sift4G

Benign

0.31

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.28

MVP

0.79

MPC

0.012

ClinPred

0.015

GERP RS

0.99

Varity_R

0.13

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over