chr6-73111383-C-A

Variant names:

• chr6-73111383-C-A
• rs1554210418
• NM_019842.4:c.1105C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_019842.4(KCNQ5):​c.1105C>A​(p.Pro369Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P369R) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: KCNQ5 NM_019842.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.83
• Publications: 1 publications found

Genes affected

KCNQ5 (HGNC:6299): (potassium voltage-gated channel subfamily Q member 5) This gene is a member of the KCNQ potassium channel gene family that is differentially expressed in subregions of the brain and in skeletal muscle. The protein encoded by this gene yields currents that activate slowly with depolarization and can form heteromeric channels with the protein encoded by the KCNQ3 gene. Currents expressed from this protein have voltage dependences and inhibitor sensitivities in common with M-currents. They are also inhibited by M1 muscarinic receptor activation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2009]

KCNQ5 Gene-Disease associations (from GenCC):

• intellectual disability, autosomal dominant 46

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-73111384-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 431388.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.815
• PP5: Variant 6-73111383-C-A is Pathogenic according to our data. Variant chr6-73111383-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 521362.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019842.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ5	NM_019842.4	MANE Select	c.1105C>A	p.Pro369Thr	missense	Exon 7 of 14	NP_062816.2
	KCNQ5	NM_001160133.2		c.1105C>A	p.Pro369Thr	missense	Exon 7 of 15	NP_001153605.1
	KCNQ5	NM_001160132.2		c.1105C>A	p.Pro369Thr	missense	Exon 7 of 14	NP_001153604.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KCNQ5	ENST00000370398.6	TSL:1 MANE Select	c.1105C>A	p.Pro369Thr	missense	Exon 7 of 14	ENSP00000359425.1
	KCNQ5	ENST00000629977.2	TSL:1	c.1105C>A	p.Pro369Thr	missense	Exon 7 of 13	ENSP00000485743.1
	KCNQ5	ENST00000370392.5	TSL:1	c.1105C>A	p.Pro369Thr	missense	Exon 7 of 9	ENSP00000359419.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457684 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725302

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33062

American (AMR) AF: 0.00 AC: 0 AN: 43452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26056

East Asian (EAS) AF: 0.00 AC: 0 AN: 39602

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110590

Other (OTH) AF: 0.00 AC: 0 AN: 60208

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Dec 14, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Intellectual disability, autosomal dominant 46 Pathogenic:1

Mar 25, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is present in gnomAD <0.001 for a dominant condition (v4: 1 heterozygote(s), 0 homozygote(s); This variant has moderate previous evidence of pathogenicity in an unrelated individual. This variant has been shown to be de novo and classified as likely pathogenic in an individual with an epileptic encephalopathy (ClinVar, PMID: 35583973); Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. The p.(Pro369Ser) and p.(Pro369Gln) variants have been classified as pathogenic by clinical laboratories (ClinVar). The p.(Pro369Arg) and p.(Pro369Leu) variants have been reported as de novo in individuals with KCNQ5-related features (PMIDs: 28669405, 36672771); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: Variant is predicted to result in a missense amino acid change from proline to threonine; This variant is heterozygous; This gene is associated with autosomal dominant disease; Variant is located in the annotated cytosolic COOH-terminal tail domain (PMID: 35583973); Loss of function and gain of function are known mechanisms of disease in this gene and are associated with intellectual developmental disorder, autosomal dominant 46 (MIM#617601; PMID: 28669405).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.68	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		7.8
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.4	D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.75
MutPred		0.47		Loss of glycosylation at P369 (P = 0.0219)
MVP		0.94
MPC		3.0
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.81
gMVP		0.98
Mutation Taster		=4/96	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554210418; hg19: chr6-73821106;