rs137854503

Variant names:

• chr9-136198798-G-A
• rs137854503
• NM_178138.6:c.629C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-136198798-G-A
• chr9-136198798-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_178138.6(LHX3):​c.629C>T​(p.Ala210Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. A210A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LHX3 NM_178138.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.67
• Publications: 6 publications found

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 Gene-Disease associations (from GenCC):

• non-acquired combined pituitary hormone deficiency with spine abnormalities

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia
• hypothyroidism due to deficient transcription factors involved in pituitary development or function

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 9-136198798-G-A is Pathogenic according to our data. Variant chr9-136198798-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 9024.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LHX3	NM_178138.6	c.629C>T	p.Ala210Val	missense_variant	Exon 5 of 6	ENST00000371748.10	NP_835258.1
LHX3	NM_014564.5	c.644C>T	p.Ala215Val	missense_variant	Exon 5 of 6		NP_055379.1
LHX3	NM_001363746.1	c.596C>T	p.Ala199Val	missense_variant	Exon 5 of 6		NP_001350675.1
LHX3	XM_017015168.1	c.557C>T	p.Ala186Val	missense_variant	Exon 5 of 6		XP_016870657.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LHX3	ENST00000371748.10	c.629C>T	p.Ala210Val	missense_variant	Exon 5 of 6	1	NM_178138.6	ENSP00000360813.4
LHX3	ENST00000371746.9	c.644C>T	p.Ala215Val	missense_variant	Exon 5 of 6	1		ENSP00000360811.3
LHX3	ENST00000619587.1	c.596C>T	p.Ala199Val	missense_variant	Exon 5 of 6	1		ENSP00000483080.1
LHX3	ENST00000645419.1	n.1454C>T		non_coding_transcript_exon_variant	Exon 4 of 5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Non-acquired combined pituitary hormone deficiency with spine abnormalities Pathogenic:1

May 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Combined pituitary hormone deficiencies, genetic form Pathogenic:1

Dec 27, 2024

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

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: LHX3 c.644C>T (p.Ala215Val) results in a non-conservative amino acid change located in the Homeodomain (IPR001356) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 240006 control chromosomes (gnomAD). c.644C>T has been reported in the literature in two siblings affected with Combined Pituitary Hormone Deficiency and this variant segregated with the disease (Pfaeffle_2007, Rajab_2008). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function and this variant affected protein function (Pfaeffle_2007). The following publications have been ascertained in the context of this evaluation (PMID: 30266296, 17327381, 18407919, 33729509). ClinVar contains an entry for this variant (Variation ID: 9024). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.95	.;D;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;M;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-3.7	D;D;.
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0010	D;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.66
MutPred		0.83		.;Gain of methylation at K211 (P = 0.0378);.;
MVP		0.98
MPC		1.9
ClinPred		0.99	D
GERP RS		2.7
Varity_R		0.87
gMVP		0.61
Mutation Taster		=28/72	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs137854503; hg19: chr9-139090644;